1,210 results on '"Genome instability"'
Search Results
2. APC/C prevents a noncanonical order of cyclin/CDK activity to maintain CDK4/6 inhibitor-induced arrest.
- Author
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Mouery, Brandon L., Baker, Eliyambuya M., Liu Mei, Wolff, Samuel C., Mills, Christine A., Fleifel, Dalia, Mulugeta, Nebyou, Herring, Laura E., and Cook, Jeanette Gowen
- Subjects
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CYCLIN-dependent kinases , *DNA synthesis , *DNA replication , *GENE expression , *PROTEOLYSIS - Abstract
Regulated cell cycle progression ensures homeostasis and prevents cancer. In proliferating cells, premature S phase entry is avoided by the E3 ubiquitin ligase anaphasepromoting complex/cyclosome (APC/C), although the APC/C substrates whose degradation restrains G1 -S progression are not fully known. The APC/C is also active in arrested cells that exited the cell cycle, but it is not clear whether APC/C maintains all types of arrest. Here, by expressing the APC/C inhibitor, EMI1, we show that APC/C activity is essential to prevent S phase entry in cells arrested by pharmacological cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition (Palbociclib). Thus, active protein degradation is required for arrest alongside repressed cell cycle gene expression. The mechanism of rapid and robust arrest bypass from inhibiting APC/C involves CDKs acting in an atypical order to inactivate retinoblastoma-mediated E2F repression. Inactivating APC/C first causes mitotic cyclin B accumulation which then promotes cyclin A expression. We propose that cyclin A is the key substrate for maintaining arrest because APC/C-resistant cyclin A, but not cyclin B, is sufficient to induce S phase entry. Cells bypassing arrest from CDK4/6 inhibition initiate DNA replication with severely reduced origin licensing. The simultaneous accumulation of S phase licensing inhibitors, such as cyclin A and geminin, with G1 licensing activators disrupts the normal order of G1-S progression. As a result, DNA synthesis and cell proliferation are profoundly impaired. Our findings predict that cancers with elevated EMI1 expression will tend to escape CDK4/6 inhibition into a premature, underlicensed S phase and suffer enhanced genome instability. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. Full-spectral genome analysis of natural killer/T cell lymphoma highlights impacts of genome instability in driving its progression
- Author
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Zegeng Chen, He Huang, Huangming Hong, Huageng Huang, Huawei Weng, Le Yu, Jian Xiao, Zhao Wang, Xiaojie Fang, Yuyi Yao, Jia-Xing Yue, and Tongyu Lin
- Subjects
Natural killer/T cell lymphoma ,Genomic alteration ,Genome instability ,Chromothripsis ,Molecular subtypes ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Natural killer/T cell lymphoma (NKTCL) is a clinically and genetically heterogeneous disease with poor prognosis. Genome sequencing and mutation characterization provides a powerful approach for patient stratification, treatment target discovery, and etiology identification. However, previous studies mostly concentrated on base-level mutations in primary NKTCL, whereas the large-scale genomic alterations in NKTCL and the mutational landscapes in relapsed/refractory NKTCL remain largely unexplored. Methods Here, we assembled whole-genome sequencing and whole-exome sequencing data from 163 patients with primary or relapsed/refractory NKTCL and compared their somatic mutational landscapes at both nucleotide and structure levels. Results Our study not only confirmed previously reported common NKTCL mutational targets like STAT3, TP53, and DDX3X but also unveiled several novel high-frequency mutational targets such as PRDM9, DST, and RBMX. In terms of the overall mutational landscape, we observed striking differences between primary and relapsed/refractory NKTCL patient groups, with the latter exhibits higher levels of tumor mutation burden, copy number variants (CNVs), and structural variants (SVs), indicating a strong signal of genomic instability. Complex structural rearrangements such as chromothripsis and focal amplification are also significantly enriched in relapsed/refractory NKTCL patients, exerting a substantial impact on prognosis. Accordingly, we devised a novel molecular subtyping system (i.e., C0–C4) with distinct prognosis by integrating potential driver mutations at both nucleotide and structural levels, which further provides an informative guidance for novel treatments that target these specific driver mutations and genome instability as a whole. Conclusions The striking differences underlying the mutational landscapes between the primary and relapsed/refractory NKTCL patients highlight the importance of genomic instability in driving the progression of NKTCL. Our newly proposed molecular subtyping system is valuable in assisting patient stratification and novel treatment design towards a better prognosis in the age of precision medicine.
- Published
- 2024
- Full Text
- View/download PDF
4. KU70 and CAF‐1 in Arabidopsis: Divergent roles in rDNA stability and telomere homeostasis.
- Author
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Závodník, Michal, Pavlištová, Veronika, Machelová, Adéla, Lyčka, Martin, Mozgová, Iva, Caklová, Karolína, Dvořáčková, Martina, and Fajkus, Jiří
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RECOMBINANT DNA , *HOMEOSTASIS , *DNA repair , *PLANT chromatin , *TELOMERES , *ARABIDOPSIS , *CHROMATIN , *BONE lengthening (Orthopedics) - Abstract
SUMMARY: Deficiency in chromatin assembly factor‐1 (CAF‐1) in plants through dysfunction of its components, FASCIATA1 and 2 (FAS1, FAS2), leads to the specific and progressive loss of rDNA and telomere repeats in plants. This loss is attributed to defective repair mechanisms for the increased DNA breaks encountered during replication, a consequence of impaired replication‐dependent chromatin assembly. In this study, we explore the role of KU70 in these processes. Our findings reveal that, although the rDNA copy number is reduced in ku70 mutants when compared with wild‐type plants, it is not markedly affected by diverse KU70 status in fas1 mutants. This is consistent with our previous characterisation of rDNA loss in fas mutants as a consequence part of the single‐strand annealing pathway of homology‐dependent repair. In stark contrast to rDNA, KU70 dysfunction fully suppresses the loss of telomeres in fas1 plants and converts telomeres to their elongated and heterogeneous state typical for ku70 plants. We conclude that the alternative telomere lengthening pathway, known to be activated in the absence of KU70, overrides progressive telomere loss due to CAF‐1 dysfunction. Significance Statement: We explore the contribution of KU70 to the specific genome instability of plants dysfunctional in chromatin assembly factor‐1 (fas1 plants) expressed as a progressive loss of telomeres and rDNA repeats. While KU dysfunction does not markedly affect rDNA instability in fas1 plants, it fully suppresses the progressive loss of telomeres in fas1 plants through activation of alternative telomere lengthening. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Cohesin — bridging the gap among gene transcription, genome stability, and human diseases.
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Di Nardo, Maddalena and Musio, Antonio
- Abstract
The intricate landscape of cellular processes governing gene transcription, chromatin organization, and genome stability is a fascinating field of study. A key player in maintaining this delicate equilibrium is the cohesin complex, a molecular machine with multifaceted roles. This review presents an in‐depth exploration of these intricate connections and their significant impact on various human diseases. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Looping forward: exploring R‐loop processing and therapeutic potential.
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Stratigi, Kalliopi, Siametis, Athanasios, and Garinis, George A.
- Abstract
Recently, there has been increasing interest in the complex relationship between transcription and genome stability, with specific attention directed toward the physiological significance of molecular structures known as R‐loops. These structures arise when an RNA strand invades into the DNA duplex, and their formation is involved in a wide range of regulatory functions affecting gene expression, DNA repair processes or cell homeostasis. The persistent presence of R‐loops, if not effectively removed, contributes to genome instability, underscoring the significance of the factors responsible for their resolution and modification. In this review, we provide a comprehensive overview of how R‐loop processing can drive either a beneficial or a harmful outcome. Additionally, we explore the potential for manipulating such structures to devise rationalized therapeutic strategies targeting the aberrant accumulation of R‐loops. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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7. Identification of different classes of genome instability suppressor genes through analysis of DNA damage response markers.
- Author
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Li, Bin-Zhong, Kolodner, Richard D, and Putnam, Christopher D
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DNA analysis , *GENOMES , *DNA damage , *GENES , *DNA repair , *CHROMOSOMAL rearrangement , *GENETIC markers , *DNA replication - Abstract
Cellular pathways that detect DNA damage are useful for identifying genes that suppress DNA damage, which can cause genome instability and cancer predisposition syndromes when mutated. We identified 199 high-confidence and 530 low-confidence DNA damage-suppressing (DDS) genes in Saccharomyces cerevisiae through a whole-genome screen for mutations inducing Hug1 expression, a focused screen for mutations inducing Ddc2 foci, and data from previous screens for mutations causing Rad52 foci accumulation and Rnr3 induction. We also identified 286 high-confidence and 394 low-confidence diverse genome instability-suppressing (DGIS) genes through a whole-genome screen for mutations resulting in increased gross chromosomal rearrangements and data from previous screens for mutations causing increased genome instability as assessed in a diversity of genome instability assays. Genes that suppress both pathways (DDS+ DGIS+) prevent or repair DNA replication damage and likely include genes preventing collisions between the replication and transcription machineries. DDS+ DGIS− genes, including many transcription-related genes, likely suppress damage that is normally repaired properly or prevent inappropriate signaling, whereas DDS− DGIS+ genes, like PIF1 , do not suppress damage but likely promote its proper, nonmutagenic repair. Thus, induction of DNA damage markers is not a reliable indicator of increased genome instability, and the DDS and DGIS categories define mechanistically distinct groups of genes. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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8. Expression of human RECQL5 in Saccharomyces cerevisiae causes transcription defects and transcription-associated genome instability.
- Author
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Lafuente-Barquero, Juan, Svejstrup, Jesper Q., Luna, Rosa, and Aguilera, Andrés
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GENE expression , *GENETIC transcription , *SACCHAROMYCES cerevisiae , *GENOMES , *PHENOTYPES , *DNA helicases - Abstract
RECQL5 is a member of the conserved RecQ family of DNA helicases involved in the maintenance of genome stability that is specifically found in higher eukaryotes and associates with the elongating RNA polymerase II. To expand our understanding of its function we expressed human RECQL5 in the yeast Saccharomyces cerevisiae, which does not have a RECQL5 ortholog. We found that RECQL5 expression leads to cell growth inhibition, increased genotoxic sensitivity and transcription-associated hyperrecombination. Chromatin immunoprecipitation and transcriptomic analysis of yeast cells expressing human RECQL5 shows that this is recruited to transcribed genes and although it causes only a weak impact on gene expression, in particular at G + C-rich genes, it leads to a transcription termination defect detected as readthrough transcription. The data indicate that the interaction between RNAPII and RECQL5 is conserved from yeast to humans. Unexpectedly, however, the RECQL5-ID mutant, previously shown to have reduced the association with RNAPII in vitro, associates with the transcribing polymerase in cells. As a result, expression of RECQL5-ID leads to similar although weaker phenotypes than wild-type RECQL5 that could be transcription-mediated. Altogether, the data suggests that RECQL5 has the intrinsic ability to function in transcription-dependent and independent genome dynamics in S. cerevisiae. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
9. The age‐related decline of helicase function—how G‐quadruplex structures promote genome instability.
- Author
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Frobel, Joana and Hänsel‐Hertsch, Robert
- Abstract
The intricate mechanisms underlying transcription‐dependent genome instability involve G‐quadruplexes (G4) and R‐loops. This perspective elucidates the potential link between these structures and genome instability in aging. The co‐occurrence of G4 DNA and RNA–DNA hybrid structures (G‐loop) underscores a complex interplay in genome regulation and instability. Here, we hypothesize that the age‐related decline of sirtuin function leads to an increase in acetylated helicases that bind to G4 DNA and RNA–DNA hybrid structures, but are less efficient in resolving them. We propose that acetylated, less active, helicases induce persistent G‐loop structures, promoting transcription‐dependent genome instability in aging. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
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10. Telomere length and micronuclei trajectories in APP/PS1 mouse model of Alzheimer's disease: Correlating with cognitive impairment and brain amyloidosis in a sexually dimorphic manner.
- Author
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Guo, Xihan, Li, Jianfei, Qi, Yanmei, Chen, Juanlin, Jiang, Minyan, Zhu, Lina, Liu, Zetong, Wang, Han, Wang, Gongwu, and Wang, Xu
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ALZHEIMER'S disease , *PITUITARY gland , *NUCLEOLUS , *COGNITION , *LABORATORY mice , *COGNITION disorders - Abstract
Although studies have demonstrated that genome instability is accumulated in patients with Alzheimer's disease (AD), the specific types of genome instability linked to AD pathogenesis remain poorly understood. Here, we report the first characterization of the age‐ and sex‐related trajectories of telomere length (TL) and micronuclei in APP/PS1 mice model and wild‐type (WT) controls (C57BL/6). TL was measured in brain (prefrontal cortex, cerebellum, pituitary gland, and hippocampus), colon and skin, and MN was measured in bone marrow in 6‐ to 14‐month‐old mice. Variation in TL was attributable to tissue type, age, genotype and, to a lesser extent, sex. Compared to WT, APP/PS1 had a significantly shorter baseline TL across all examined tissues. TL was inversely associated with age in both genotypes and TL shortening was accelerated in brain of APP/PS1. Age‐related increase of micronuclei was observed in both genotypes but was accelerated in APP/PS1. We integrated TL and micronuclei data with data on cognition performance and brain amyloidosis. TL and micronuclei were linearly correlated with cognition performance or Aβ40 and Aβ42 levels in both genotypes but to a greater extent in APP/PS1. These associations in APP/PS1 mice were dominantly driven by females. Together, our findings provide foundational knowledge to infer the TL and micronuclei trajectories in APP/PS1 mice during disease progression, and strongly support that TL attrition and micronucleation are tightly associated with AD pathogenesis in a female‐biased manner. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
11. Full-spectral genome analysis of natural killer/T cell lymphoma highlights impacts of genome instability in driving its progression.
- Author
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Chen, Zegeng, Huang, He, Hong, Huangming, Huang, Huageng, Weng, Huawei, Yu, Le, Xiao, Jian, Wang, Zhao, Fang, Xiaojie, Yao, Yuyi, Yue, Jia-Xing, and Lin, Tongyu
- Subjects
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T cells , *WHOLE genome sequencing , *DNA copy number variations , *KILLER cells , *GENOMES , *GENE amplification , *LYMPHOMAS , *NUCLEOTIDE sequencing - Abstract
Background: Natural killer/T cell lymphoma (NKTCL) is a clinically and genetically heterogeneous disease with poor prognosis. Genome sequencing and mutation characterization provides a powerful approach for patient stratification, treatment target discovery, and etiology identification. However, previous studies mostly concentrated on base-level mutations in primary NKTCL, whereas the large-scale genomic alterations in NKTCL and the mutational landscapes in relapsed/refractory NKTCL remain largely unexplored. Methods: Here, we assembled whole-genome sequencing and whole-exome sequencing data from 163 patients with primary or relapsed/refractory NKTCL and compared their somatic mutational landscapes at both nucleotide and structure levels. Results: Our study not only confirmed previously reported common NKTCL mutational targets like STAT3, TP53, and DDX3X but also unveiled several novel high-frequency mutational targets such as PRDM9, DST, and RBMX. In terms of the overall mutational landscape, we observed striking differences between primary and relapsed/refractory NKTCL patient groups, with the latter exhibits higher levels of tumor mutation burden, copy number variants (CNVs), and structural variants (SVs), indicating a strong signal of genomic instability. Complex structural rearrangements such as chromothripsis and focal amplification are also significantly enriched in relapsed/refractory NKTCL patients, exerting a substantial impact on prognosis. Accordingly, we devised a novel molecular subtyping system (i.e., C0–C4) with distinct prognosis by integrating potential driver mutations at both nucleotide and structural levels, which further provides an informative guidance for novel treatments that target these specific driver mutations and genome instability as a whole. Conclusions: The striking differences underlying the mutational landscapes between the primary and relapsed/refractory NKTCL patients highlight the importance of genomic instability in driving the progression of NKTCL. Our newly proposed molecular subtyping system is valuable in assisting patient stratification and novel treatment design towards a better prognosis in the age of precision medicine. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
12. Follicular DNA Damage and Pesticide Exposure Among Latinx Children in Rural and Urban Communities
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Lepetit, Cassandra, Gaber, Mohamed, Zhou, Ke, Chen, Haiying, Holmes, Julia, Summers, Phillip, Anderson, Kim A., Scott, Richard P., Pope, Carey N., Hester, Kirstin, Laurienti, Paul J., Quandt, Sara A., Arcury, Thomas A., and Vidi, Pierre-Alexandre
- Published
- 2024
- Full Text
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13. SSBlazer: a genome-wide nucleotide-resolution model for predicting single-strand break sites
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Sheng Xu, Junkang Wei, Siqi Sun, Jizhou Zhang, Ting-Fung Chan, and Yu Li
- Subjects
Single-strand break ,Genome instability ,Nucleotide-resolution model ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Single-strand breaks are the major DNA damage in the genome and serve a crucial role in various biological processes. To reveal the significance of single-strand breaks, multiple sequencing-based single-strand break detection methods have been developed, which are costly and unfeasible for large-scale analysis. Hence, we propose SSBlazer, an explainable and scalable deep learning framework for single-strand break site prediction at the nucleotide level. SSBlazer is a lightweight model with robust generalization capabilities across various species and is capable of numerous unexplored SSB-related applications.
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- 2024
- Full Text
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14. Repression of the SUMO-conjugating enzyme UBC9 is associated with lowered double minutes and reduced tumor progression
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Yusi Wang, Hongyan Zou, Wei Ji, Min Huang, Benhui You, Nan Sun, Yuandong Qiao, Peng Liu, Lidan Xu, Xuelong Zhang, Mengdi Cai, Ye Kuang, Songbin Fu, Wenjing Sun, Xueyuan Jia, and Jie Wu
- Subjects
SUMOylation ,double minutes ,UBC9 ,genome instability ,DNA damage repair ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
ABSTRACTDouble minutes (DMs), extrachromosomal gene fragments found within certain tumors, have been noted to carry onco- and drug resistance genes contributing to tumor pathogenesis and progression. After screening for SUMO-related molecule expression within various tumor sample and cell line databases, we found that SUMO-conjugating enzyme UBC9 has been associated with genome instability and tumor cell DM counts, which was confirmed both in vitro and in vivo. Karyotyping determined DM counts post-UBC9 knockdown or SUMOylation inhibitor 2-D08, while RT-qPCR and Western blot were used to measure DM-carried gene expression in vitro. In vivo, fluorescence in situ hybridization (FISH) identified micronucleus (MN) expulsion. Western blot and immunofluorescence staining were then used to determine DNA damage extent, and a reporter plasmid system was constructed to detect changes in homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. Our research has shown that UBC9 inhibition is able to attenuate DM formation and lower DM-carried gene expression, in turn reducing tumor growth and malignant phenotype, via MN efflux of DMs and lowering NHEJ activity to increase DNA damage. These findings thus reveal a relationship between heightened UBC9 activity, increased DM counts, and tumor progression, providing a potential approach for targeted therapies, via UBC9 inhibition.
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- 2024
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15. Role of AT‐rich interaction domain 1A in gastric cancer immunotherapy: Preclinical and clinical perspectives.
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Zhang, Xuemei, Zhang, Youzhi, Zhang, Qiaoyun, Lu, Mengyao, Chen, Yuan, Zhang, Xiaoyu, and Zhang, Peng
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STOMACH cancer ,IMMUNE checkpoint inhibitors ,IMMUNOTHERAPY ,MONOCLONAL antibodies ,TUMOR microenvironment - Abstract
The application of immune checkpoint inhibitor (ICI) using monoclonal antibodies has brought about a profound transformation in the clinical outcomes for patients grappling with advanced gastric cancer (GC). Nonetheless, despite these achievements, the quest for effective functional biomarkers for ICI therapy remains constrained. Recent research endeavours have shed light on the critical involvement of modified epigenetic regulators in the pathogenesis of gastric tumorigenesis, thus providing a glimpse into potential biomarkers. Among these regulatory factors, AT‐rich interaction domain 1A (ARID1A), a pivotal constituent of the switch/sucrose non‐fermentable (SWI/SNF) complex, has emerged as a promising candidate. Investigations have unveiled the pivotal role of ARID1A in bridging the gap between genome instability and the reconfiguration of the tumour immune microenvironment, culminating in an enhanced response to ICI within the landscape of gastric cancer treatment. This all‐encompassing review aims to dissect the potential of ARID1A as a valuable biomarker for immunotherapeutic approaches in gastric cancer, drawing from insights garnered from both preclinical experimentation and clinical observations. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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16. Overexpression of SMYD3 Promotes Autosomal Dominant Polycystic Kidney Disease by Mediating Cell Proliferation and Genome Instability.
- Author
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Agborbesong, Ewud, Zhou, Julie Xia, Zhang, Hongbing, Li, Linda Xiaoyan, Harris, Peter C., Calvet, James P., and Li, Xiaogang
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POLYCYSTIC kidney disease ,CELL proliferation ,TUBULINS ,GENOMES ,CHRONIC kidney failure ,GENETIC overexpression - Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder worldwide and progresses to end-stage renal disease (ESRD). However, its precise mechanism is not fully understood. In recent years, epigenetic reprogramming has drawn increasing attention regarding its effect on cyst growth. However, considering the complexity of epigenetic mechanisms and the broad range of alterations of epigenetic components in ADPKD, identifying more specific epigenetic factors and understanding how they are mechanistically linked to promote cyst growth is relevant for the development of treatment for ADPKD. Here, we find that the histone methyltransferase SMYD3, which activates gene transcription via histone H3 lysine 4 trimethylation (H3K4me3), is upregulated in PKD1 mutant mouse and human ADPKD kidneys. Genetic knockout of SMYD3 in a PKD1 knockout mouse model delayed cyst growth and improved kidney function compared with PKD1 single knockout mouse kidneys. Immunostaining and Western blot assays indicated that SMYD3 regulated PKD1-associated signaling pathways associated with proliferation, apoptosis, and cell cycle effectors in PKD1 mutant renal epithelial cells and tissues. In addition, we found that SMYD3 localized to the centrosome and regulated mitosis and cytokinesis via methylation of α-tubulin at lysine 40. In addition, SMYD3 regulated primary cilia assembly in PKD1 mutant mouse kidneys. In summary, our results demonstrate that overexpression of SMYD3 contributes to cyst progression and suggests targeting SMYD3 as a potential therapeutic strategy for ADPKD. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
17. A nematode model to evaluate microdeletion phenotype expression.
- Author
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Antkowiak, Katianna R, Coskun, Peren, Noronha, Sharon T, Tavella, Davide, Massi, Francesca, and Ryder, Sean P
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PHENOTYPES , *GENETIC models , *GENETIC variation , *GENOME editing , *ANIMAL mutation , *CAENORHABDITIS elegans , *CHROMOSOMAL translocation - Abstract
Microdeletion syndromes are genetic diseases caused by multilocus chromosomal deletions too small to be detected by karyotyping. They are typified by complex pleiotropic developmental phenotypes that depend both on the extent of the deletion and variations in genetic background. Microdeletion alleles cause a wide array of consequences involving multiple pathways. How simultaneous haploinsufficiency of numerous adjacent genes leads to complex and variable pleiotropic phenotypes is not well understood. CRISPR/Cas9 genome editing has been shown to induce microdeletion-like alleles at a meaningful rate. Here, we describe a microdeletion allele in Caenorhabditis elegans recovered during a CRISPR/Cas9 genome editing experiment. We mapped the allele to chromosome V, balanced it with a reciprocal translocation crossover suppressor, and precisely defined the breakpoint junction. The allele simultaneously removes 32 protein-coding genes, yet animals homozygous for this mutation are viable as adults. Homozygous animals display a complex phenotype including maternal effect lethality, producing polynucleated embryos that grow into uterine tumors, vulva morphogenesis defects, body wall distensions, uncoordinated movement, and a shortened life span typified by death by bursting. Our work provides an opportunity to explore the complexity and penetrance of microdeletion phenotypes in a simple genetic model system. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
18. Investigating chromosomal instability in long-term survivors with glioblastoma and grade 4 astrocytoma.
- Author
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Spoor, Jochem K. H., den Braber, May, Dirven, Clemens M. F., Pennycuick, Adam, Bartkova, Jirina, Bartek, Jiri, van Dis, Vera, van den Bosch, Thierry P. P., Leenstra, Sieger, and Venkatesan, Subramanian
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ASTROCYTOMAS ,GLIOBLASTOMA multiforme ,ISOCITRATE dehydrogenase ,GLIOMAS ,PROGNOSIS - Abstract
Background: Only a small group of patients with glioblastoma multiforme (GBM) survives more than 36 months, so-called long-term survivors. Recent studies have shown that chromosomal instability (CIN) plays a prognostic and predictive role among different cancer types. Here, we compared histological (chromosome missegregation) and bioinformatic metrics (CIN signatures) of CIN in tumors of GBM typical survivors (=36 months overall survival), GBM long-term survivors and isocitrate dehydrogenase (IDH)-mutant grade 4 astrocytomas. Methods: Tumor sections of all gliomas were examined for anaphases and chromosome missegregation. Further CIN signature activity analysis in the The Cancer Genome Atlas (TCGA)-GBM cohort was performed. Results: Our data show that chromosome missegregation is pervasive in high grade gliomas and is not different between the 3 groups. We find only limited evidence of altered CIN levels in tumors of GBM long-term survivors relative to the other groups, since a significant depletion in CIN signature 11 relative to GBM typical survivors was the only alteration detected. In contrast, within IDH-mutant grade 4 astrocytomas we detected a significant enrichment of CIN signature 5 and 10 activities and a depletion of CIN signature 1 activity relative to tumors of GBM typical survivors. Conclusions: Our data suggest that CIN is pervasive in high grade gliomas, however this is unlikely to be a major contributor to the phenomenon of long-term survivorship in GBM. Nevertheless, further evaluation of specific types of CIN (signatures) could have prognostic value in patients suffering from grade 4 gliomas. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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19. Genomic variation in neurons.
- Author
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Zolzaya, Sunjidmaa, Narumoto, Ayano, and Katsuyama, Yu
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LONGEVITY , *FETAL death , *NEURONS , *NEUROLOGICAL disorders , *NEURAL development , *MOSAICISM , *FACTOR analysis - Abstract
Neurons born during the fetal period have extreme longevity and survive until the death of the individual because the human brain has highly limited tissue regeneration. The brain is comprised of an enormous variety of neurons each exhibiting different morphological and physiological characteristics and recent studies have further reported variations in their genome including chromosomal abnormalities, copy number variations, and single nucleotide mutations. During the early stages of brain development, the increasing number of neurons generated at high speeds has been proposed to lead to chromosomal instability. Additionally, mutations in the neuronal genome can occur in the mature brain. This observed genomic mosaicism in the brain can be produced by multiple endogenous and environmental factors and careful analyses of these observed variations in the neuronal genome remain central for our understanding of the genetic basis of neurological disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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20. Effects of genome instability of parental CHO cell clones on chromosome number distribution and recombinant protein production in parent-derived subclones.
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Yamano-Adachi, Noriko, Hata, Hirofumi, Nakanishi, Yuto, and Omasa, Takeshi
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CHROMOSOMES , *RECOMBINANT proteins , *CHO cell , *MOLECULAR cloning , *CELL lines , *BIOPHARMACEUTICS , *SPECIES distribution , *GENOMES - Abstract
Chinese hamster ovary (CHO) cells are the de facto standard host cells for biopharmaceuticals, and there is great interest in developing methods for constructing stable production cell lines. In this study, clones with a wide chromosome number distribution were selected from isolated antibody-producing strains, and subclones obtained from these clones were evaluated. The transgene copy number varied between the subclones. Even among subclones with similar copy numbers of antibody genes and maintained insertion sites, clones with different productivity were generated. Although the chromosome number distribution differed between these subclones, there was no correlation between the variability in chromosome number after cloning (genome instability) and productivity. Most of the subclones obtained from a parental strain with a wide chromosome number had the same wide chromosome number distribution as the parental strain. Less frequently, cells with less variation (remaining in one distribution) in chromosome number were isolated from cells with a wide chromosome number distribution, from which subclones with less variation in chromosome number were obtained when subcloning was performed again. These results imply that the characteristics of clones with chromosomal instability are inherited by subclones, and thus provide a better understanding of cell line stability/instability. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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21. Response to Replication Stress and Maintenance of Genome Stability by WRN, the Werner Syndrome Protein
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David K. Orren and Amrita Machwe
- Subjects
Werner syndrome ,RecQ helicases ,genome instability ,DNA repair ,homologous recombination ,replication stress ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Werner syndrome (WS) is an autosomal recessive disease caused by loss of function of WRN. WS is a segmental progeroid disease and shows early onset or increased frequency of many characteristics of normal aging. WRN possesses helicase, annealing, strand exchange, and exonuclease activities and acts on a variety of DNA substrates, even complex replication and recombination intermediates. Here, we review the genetics, biochemistry, and probably physiological functions of the WRN protein. Although its precise role is unclear, evidence suggests WRN plays a role in pathways that respond to replication stress and maintain genome stability particularly in telomeric regions.
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- 2024
- Full Text
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22. Cytogenetic Effects in the Bone Marrow of Animals Living in Conditions of Increased Natural Background Radiation.
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Bashlykova, L. A. and Raskosha, O. V.
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BONE marrow , *BACKGROUND radiation , *KARYOTYPES , *LIVING conditions , *BONE marrow cells , *CHROMOSOME abnormalities - Abstract
We studied the cytogenetic effects in the bone marrow cells of root voles (Alexandromys (Microtus) oeconomus Pall.) that lived in areas contaminated with uranium and radium as a result of the operation of radium mining (radium site) and the storage of its waste (uranium–radium site) (Komi Republic). The level and nature of mutational effects in voles from radioactively contaminated areas indicates the persistence of an increased frequency of chromosome aberrations and the appearance of individuals with an altered karyotype, which indicates genetic instability. When determining the nature of the dynamics of the mutation process in the populations studied, a high frequency of cells with micronuclei was noted in voles from the radium area, with the exception of the phase of population decline. In experiments with the use of provocative factors of chemical (urethane) and radiation (acute γ-irradiation) nature, an increase in the stability of bone marrow cells of animals living in conditions of increased background radiation has been shown. [ABSTRACT FROM AUTHOR]
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- 2023
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23. The Composition of Micronuclei in T-Lymphocytes in Women Affected by Chronic Radiation Exposure.
- Author
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Akhmadullina, Yu. R.
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NUCLEOLUS , *RADIATION exposure , *T cells , *BONE marrow , *CHROMOSOMES , *GENETIC toxicology , *X chromosome , *DOSE-response relationship (Radiation) - Abstract
We studied the chromosomal composition of micronuclei the peripheral blood T-lymphocytes of women chronically exposed due to their residence in the Techa riverside villages in the Southern Urals (cumulative doses to red bone marrow (RBM) ranged from 0.73 to 1.93 Gy, the age range of women was 73 to 82 years). Micronucleus assay with cytochalasin block and multicolor staining of preparations (mFISH method) was used to identify each chromosome. On average, the exposed women had more chromosomes in the micronucleus than those in the comparison group (p = 0.001). The probability of micronucleus formation from chromosomes is not equal if we compare the group of exposed women and the comparison group. The biggest number of micronuclei is monocolor; i.e., they are formed from the material of a single chromosome. In 44–55% of cases, monocolor micronuclei are formed by the X chromosome; in 4–7%, by the 16th chromosome. In the groups studied, the 2nd, 4th, 10th, 16th, and X chromosomes occur more frequently in the multicolor micronuclei. The second chromosome occurs statistically significantly more frequently in monocolor micronuclei in exposed women than in those from the comparison group (p = 0.001); the 6th, 17th, and 18th chromosomes occur statistically significantly more frequently in multicolor micronuclei (p = 0.0036, p = 0.023, p = 0.02, respectively). [ABSTRACT FROM AUTHOR]
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- 2023
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24. Identification of Genomic Instability in Cows Infected with BVD Virus.
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Kępka, Katarzyna, Wójcik, Ewa, and Wysokińska, Anna
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BOVINE viral diarrhea virus , *BOVINE viral diarrhea , *SISTER chromatid exchange , *COWS , *HEALTH of cattle , *MILKING , *DNA damage - Abstract
Simple Summary: The aim of the study was to identify the genomic instability in cows with reproductive disorders following infection with the BVD virus. The genomic stability was analyzed using the sister chromatid exchange, fragile sites, and comet assays. Statistically significant differences were noted between the groups. Of the three assays, the comet assay proved to be the most sensitive for identifying DNA damage in the animals. An important factor for dairy cattle farmers is the profitability of cattle rearing, which is influenced by the animals' health and reproductive parameters, as well as their genomic stability and integrity. Bovine viral diarrhea (BVD) negatively affects the health of dairy cattle and causes reproductive problems. The aim of the study was to identify genomic instability in cows with reproductive disorders following infection with the BVD virus. The material for analysis was peripheral blood from Holstein-Friesian cows with reproductive problems, which had tested positive for BVD, and from healthy cows with no reproductive problems, which had tested negative for BVD. Three cytogenetic tests were used: the sister chromatid exchange assay, fragile sites assay, and comet assay. Statistically significant differences were noted between the groups and between the individual cows in the average frequency of damage. The assays were good biomarkers of genomic stability and enabled the identification of individuals with an increased frequency of damage to genetic material that posed a negative impact on their health. The assays can be used to prevent disease during its course and evaluate the genetic resistance of animals. This is especially important for the breeder, both for economic and breeding reasons. Of the three assays, the comet assay proved to be the most sensitive for identifying DNA damage in the animals. [ABSTRACT FROM AUTHOR]
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- 2023
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25. Cellular Responses to Widespread DNA Replication Stress.
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Nickoloff, Jac A., Jaiswal, Aruna S., Sharma, Neelam, Williamson, Elizabeth A., Tran, Manh T., Arris, Dominic, Yang, Ming, and Hromas, Robert
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DNA replication , *DOUBLE-strand DNA breaks , *DNA polymerases , *DNA repair , *DNA structure , *DNA damage , *APOPTOSIS - Abstract
Replicative DNA polymerases are blocked by nearly all types of DNA damage. The resulting DNA replication stress threatens genome stability. DNA replication stress is also caused by depletion of nucleotide pools, DNA polymerase inhibitors, and DNA sequences or structures that are difficult to replicate. Replication stress triggers complex cellular responses that include cell cycle arrest, replication fork collapse to one-ended DNA double-strand breaks, induction of DNA repair, and programmed cell death after excessive damage. Replication stress caused by specific structures (e.g., G-rich sequences that form G-quadruplexes) is localized but occurs during the S phase of every cell division. This review focuses on cellular responses to widespread stress such as that caused by random DNA damage, DNA polymerase inhibition/nucleotide pool depletion, and R-loops. Another form of global replication stress is seen in cancer cells and is termed oncogenic stress, reflecting dysregulated replication origin firing and/or replication fork progression. Replication stress responses are often dysregulated in cancer cells, and this too contributes to ongoing genome instability that can drive cancer progression. Nucleases play critical roles in replication stress responses, including MUS81, EEPD1, Metnase, CtIP, MRE11, EXO1, DNA2-BLM, SLX1-SLX4, XPF-ERCC1-SLX4, Artemis, XPG, FEN1, and TATDN2. Several of these nucleases cleave branched DNA structures at stressed replication forks to promote repair and restart of these forks. We recently defined roles for EEPD1 in restarting stressed replication forks after oxidative DNA damage, and for TATDN2 in mitigating replication stress caused by R-loop accumulation in BRCA1-defective cells. We also discuss how insights into biological responses to genome-wide replication stress can inform novel cancer treatment strategies that exploit synthetic lethal relationships among replication stress response factors. [ABSTRACT FROM AUTHOR]
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- 2023
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26. Impaired dNKAP function drives genome instability and tumorigenic growth in Drosophila epithelia.
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Guo, Ting, Miao, Chen, Liu, Zhonghua, Duan, Jingwei, Ma, Yanbin, Zhang, Xiao, Yang, Weiwei, Xue, Maoguang, Deng, Qiannan, Guo, Pengfei, Xi, Yongmei, Yang, Xiaohang, Huang, Xun, and Ge, Wanzhong
- Abstract
Mutations or dysregulated expression of NF-kappaB-activating protein (NKAP) family genes have been found in human cancers. How NKAP family gene mutations promote tumor initiation and progression remains to be determined. Here, we characterized dNKAP, the Drosophila homolog of NKAP, and showed that impaired dNKAP function causes genome instability and tumorigenic growth in a Drosophila epithelial tumor model. dNKAP -knockdown wing imaginal discs exhibit tumorigenic characteristics, including tissue overgrowth, cell-invasive behavior, abnormal cell polarity, and cell adhesion defects. dNKAP knockdown causes both R-loop accumulation and DNA damage, indicating the disruption of genome integrity. Further analysis showed that dNKAP knockdown induces c-Jun N-terminal kinase (JNK)-dependent apoptosis and causes aberrant cell proliferation in distinct cell populations. Activation of the Notch and JAK/STAT signaling pathways contributes to the tumorigenic growth of dNKAP -knockdown tissues. Furthermore, JNK signaling is essential for dNKAP depletion-mediated cell invasion. Transcriptome analysis of dNKAP -knockdown tissues confirmed the misregulation of signaling pathways involved in promoting tumorigenesis and revealed abnormal regulation of metabolic pathways. dNKAP knockdown and oncogenic Ras, Notch, or Yki mutations show synergies in driving tumorigenesis, further supporting the tumor-suppressive role of dNKAP. In summary, this study demonstrates that dNKAP plays a tumor-suppressive role by preventing genome instability in Drosophila epithelia and thus provides novel insights into the roles of human NKAP family genes in tumor initiation and progression. [ABSTRACT FROM AUTHOR]
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- 2023
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27. The Response of the Cell Genome of Endometrial Mesenchymal Stem Cells to the Procedure of Long-Term Cyropreservation.
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Grinchuk, T. M., Shorokhova, M. A., and Pugovkina, N. A.
- Abstract
Information about the effect of cryopreservation on cellular functions and the genetic apparatus of cells of differing genesis is not unambiguous and is in the process of accumulation. This work is aimed at studying the effect of long-term storage (7 years) in the frozen state of human endometrial mesenchymal stem cells (eMSCs) on the stability of their genome in vitro. The results showed destabilization of the karyotype structure in the descendants of cells after their thawing, namely, aneupolyploidization of the chromosome set; increased fragility of chromosomes, resulting in a huge pool of aberrant chromosomes; and impaired condensation in homologues. Chromosomal breakdowns affecting the centromeric regions were in some cases accompanied by the preservation of genetic material in the form of independent chromosomes. Almost all chromosomes of the set were involved in the process of destabilization of the eMSC cell genome. It has been shown that the procedure of long-term cryopreservation can become an inducer of premature cellular aging of eMSCs after their thawing. Comparison of the data obtained with the results of karyotyping of transformed Chinese hamster cells that underwent a similar procedure led to the conclusion that cryopreservation for biological systems can be a stress that induces heterogeneous genetic defects at the karyotype level. The response of the genome of cells of different origin to the same conditions of cryopreservation may differ. [ABSTRACT FROM AUTHOR]
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- 2023
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28. Non-B DNA structures as a booster of genome instability.
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Duardo, Renée C., Guerra, Federico, Pepe, Simona, and Capranico, Giovanni
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DNA structure , *GENOMES , *NUCLEIC acids , *DNA replication , *CHROMOSOME abnormalities , *HAIRPIN (Genetics) - Abstract
Non-canonical secondary structures (NCSs) are alternative nucleic acid structures that differ from the canonical B-DNA conformation. NCSs often occur in repetitive DNA sequences and can adopt different conformations depending on the sequence. The majority of these structures form in the context of physiological processes, such as transcription-associated R-loops, G4s, as well as hairpins and slipped-strand DNA, whose formation can be dependent on DNA replication. It is therefore not surprising that NCSs play important roles in the regulation of key biological processes. In the last years, increasing published data have supported their biological role thanks to genome-wide studies and the development of bioinformatic prediction tools. Data have also highlighted the pathological role of these secondary structures. Indeed, the alteration or stabilization of NCSs can cause the impairment of transcription and DNA replication, modification in chromatin structure and DNA damage. These events lead to a wide range of recombination events, deletions, mutations and chromosomal aberrations, well-known hallmarks of genome instability which are strongly associated with human diseases. In this review, we summarize molecular processes through which NCSs trigger genome instability, with a focus on G-quadruplex, i-motif, R-loop, Z-DNA, hairpin, cruciform and multi-stranded structures known as triplexes. [ABSTRACT FROM AUTHOR]
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- 2023
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29. R-Loops in Genome Instability and Cancer.
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Li, Fang, Zafar, Alyan, Luo, Liang, Denning, Ariana Maria, Gu, Jun, Bennett, Ansley, Yuan, Fenghua, and Zhang, Yanbin
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TUMOR diagnosis , *TUMOR treatment , *GENETIC mutation , *DNA , *CARCINOGENESIS , *ONCOGENES , *RNA , *MEDICAL technology , *NEOPLASTIC cell transformation , *CELL proliferation , *TUMORS ,TUMOR genetics - Abstract
Simple Summary: R-loops are three-stranded structures consisting of an RNA–DNA hybrid and an unpaired single-stranded DNA (ssDNA), with biological implications in cellular physiology and pathological conditions. R-loops interfere with DNA repair pathways and activate oncogenes, leading to dysregulated cell proliferation, genome instability, and cancer development. R-loops accumulate in several types of cancer cells, including breast, ovarian, prostate, and lung cancer. Studying the biological roles of R-loops in cancer development is potentially beneficial for innovative diagnostic and treatment approaches for cancer. In this review, we focus on recent advances in R-loops' roles in genome instability, DNA repair, and oncogenic events. R-loops are unique, three-stranded nucleic acid structures that primarily form when an RNA molecule displaces one DNA strand and anneals to the complementary DNA strand in a double-stranded DNA molecule. R-loop formation can occur during natural processes, such as transcription, in which the nascent RNA molecule remains hybridized with the template DNA strand, while the non-template DNA strand is displaced. However, R-loops can also arise due to many non-natural processes, including DNA damage, dysregulation of RNA degradation pathways, and defects in RNA processing. Despite their prevalence throughout the whole genome, R-loops are predominantly found in actively transcribed gene regions, enabling R-loops to serve seemingly controversial roles. On one hand, the pathological accumulation of R-loops contributes to genome instability, a hallmark of cancer development that plays a role in tumorigenesis, cancer progression, and therapeutic resistance. On the other hand, R-loops play critical roles in regulating essential processes, such as gene expression, chromatin organization, class-switch recombination, mitochondrial DNA replication, and DNA repair. In this review, we summarize discoveries related to the formation, suppression, and removal of R-loops and their influence on genome instability, DNA repair, and oncogenic events. We have also discussed therapeutical opportunities by targeting pathological R-loops. [ABSTRACT FROM AUTHOR]
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- 2023
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30. Copy Number Variation That Influences the Ionizing Radiation Sensitivity of Oral Squamous Cell Carcinoma.
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Izumi, Tadahide, Rychahou, Piotr, Chen, Li, Smith, Molly H., and Valentino, Joseph
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DNA repair , *SQUAMOUS cell carcinoma , *IONIZING radiation , *DOUBLE-strand DNA breaks , *RADIOTHERAPY safety , *PROTEIN arginine methyltransferases , *HUMAN genome - Abstract
Genome instability in cancer cells causes not only point mutations but also structural variations of the genome, including copy number variations (CNVs). It has recently been proposed that CNVs arise in cancer to adapt to a given microenvironment to survive. However, how CNV influences cellular resistance against ionizing radiation remains unknown. PRMT5 (protein arginine methyltransferase 5) and APE1 (apurinic/apyrimidinic endonuclease 1), which enhance repair of DNA double-strand breaks and oxidative DNA damage, are closely localized in the chromosome 14 of the human genome. In this study, the genomics data for the PRMT5 and APE1 genes, including their expression, CNVs, and clinical outcomes, were analyzed using TCGA's data set for oral squamous cell carcinoma patients. The two genes were found to share almost identical CNV values among cancer tissues from oral squamous cell carcinoma (OSCC) patients. Levels of expression of PRMT5 and APE1 in OSCC tissues are highly correlated in cancer but not in normal tissues, suggesting that regulation of PRMT5 and APE1 were overridden by the extent of CNV in the PRMT5-APE1 genome region. High expression levels of PRMT5 and APE1 were both associated with poor survival outcomes after radiation therapy. Simultaneous down-regulation of PRMT5 and APE1 synergistically hampered DNA double-strand break repair and sensitized OSCC cell lines to X-ray irradiation in vitro and in vivo. These results suggest that the extent of CNV in a particular genome region significantly influence the radiation resistance of cancer cells. Profiling CNV in the PRMT5-APE1 genome region may help us to understand the mechanism of the acquired radioresistance of tumor cells, and raises the possibility that simultaneous inhibition of PRMT5 and APE1 may increase the efficacy of radiation therapy. [ABSTRACT FROM AUTHOR]
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- 2023
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31. Self-inflicted DNA breaks in cell differentiation and cancer.
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Benada, Jan, Alsowaida, Dalal, Megeney, Lynn A., and Sørensen, Claus S.
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CANCER cell differentiation , *DNA repair , *GENETIC variation , *ENZYME activation , *CANCER cells , *DNA damage - Abstract
Nucleases are employed physiologically to inflict DNA lesions that promote processes such as apoptosis, the evolution of the germline, and adaptation of the immune system. Increasing evidence suggests that nucleases also inflict regulated DNA damage in other processes such as during cell differentiation. During cancer development, nuclease-mediated genomic lesions promote tumorigenesis through enhancing genome instability. Cancer cells can hijack nucleases such as caspase-activated DNase (CAD) to activate DNA damage response checkpoints to induce cell-cycle arrest and thus promote cancer cell survival. Self-inflicted DNA strand breaks are canonically linked with cell death pathways and the establishment of genetic diversity in immune and germline cells. Moreover, this form of DNA damage is an established source of genome instability in cancer development. However, recent studies indicate that nonlethal self-inflicted DNA strand breaks play an indispensable but underappreciated role in a variety of cell processes, including differentiation and cancer therapy responses. Mechanistically, these physiological DNA breaks originate from the activation of nucleases, which are best characterized for inducing DNA fragmentation in apoptotic cell death. In this review, we outline the emerging biology of one critical nuclease, caspase-activated DNase (CAD), and how directed activation or deployment of this enzyme can lead to divergent cell fate outcomes. [ABSTRACT FROM AUTHOR]
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- 2023
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32. Relationship of radiation-induced genomic instability and antioxidant production in the chamomile plant.
- Author
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Sokolova, Daryna A., Halych, Taras V., Zhuk, Vladyslav V., and Kravets, Alexandra P.
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DOSE-response relationship (Radiation) , *GENE rearrangement , *RADIATION exposure , *DNA structure , *FLOWERING of plants , *EXPOSURE dose , *REACTIVE oxygen species , *LENTILS , *ELLAGIC acid - Abstract
To verify the hypothesis about the preservation of signs of radiation-induced genomic instability at the flowering stage of the chamomile plant after pre-sowing seed irradiation, the interaction of dose-dependent changes in the level of DNA damage and stimulation of antioxidant production. The study was carried out on two genotypes of chamomile, Perlyna Lisostepu variety and its mutant, using pre-sowing seed radiation exposure at dose levels 5–15 Gy. Studies of the rearrangement of the primary DNA structure of under different doses were studied on plant tissues at the flowering stage using – ISSR and RAPD DNA markers. Dose-dependent changes relative to the control of the amplicons' spectra were analyzed using the Jacquard similarity index. Antioxidants such as flavonoids and phenols were isolated from pharmaceutical raw materials (inflorescences) using traditional methods. Preservation of multiple DNA damages at the stage of plant flowering under pre-sowing seed irradiation at low doses was confirmed. It was found that the largest rearrangements of the primary DNA structure of both genotypes, manifested in reduced similarity with the control spectra of amplicons, were observed under irradiation dose levels 5–10 Gy. There was a tendency to approach this indicator to the control under 15 Gy dose, which means increasing efficiency of the reparative processes. The relationship between the polymorphism of the primary structure of DNA by ISSR-RAPD-markers in different genotypes and the nature of its rearrangement under radiation exposure was shown. Dose dependences of changes in the specific content of antioxidants were non-monotonic with a maximum at 5–10 Gy. Comparison of dose dependences of changes in the coefficient of similarity of the spectrum of amplicons between irradiated and control variants with nonmonotonic dose curves in the specific content of antioxidants allowed to suggest that there was the antioxidant protection stimulation under the doses corresponding to low efficiency of repair processes. The decrease in the specific content of antioxidants followed the restoration of the genetic material normal state. The interpretation of the identified phenomenon has been based on both known connection between the effects of genomic instability and the increasing yield of the reactive oxygen species and general principles of antioxidant protection. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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33. Investigating chromosomal instability in long-term survivors with glioblastoma and grade 4 astrocytoma
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Jochem K. H. Spoor, May den Braber, Clemens M. F. Dirven, Adam Pennycuick, Jirina Bartkova, Jiri Bartek, Vera van Dis, Thierry P. P. van den Bosch, Sieger Leenstra, and Subramanian Venkatesan
- Subjects
high grade glioma ,glioblastoma multiforme ,astrocytoma ,chromosomal instability ,genome instability ,IDH ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundOnly a small group of patients with glioblastoma multiforme (GBM) survives more than 36 months, so-called long-term survivors. Recent studies have shown that chromosomal instability (CIN) plays a prognostic and predictive role among different cancer types. Here, we compared histological (chromosome missegregation) and bioinformatic metrics (CIN signatures) of CIN in tumors of GBM typical survivors (≤36 months overall survival), GBM long-term survivors and isocitrate dehydrogenase (IDH)-mutant grade 4 astrocytomas.MethodsTumor sections of all gliomas were examined for anaphases and chromosome missegregation. Further CIN signature activity analysis in the The Cancer Genome Atlas (TCGA)-GBM cohort was performed.ResultsOur data show that chromosome missegregation is pervasive in high grade gliomas and is not different between the 3 groups. We find only limited evidence of altered CIN levels in tumors of GBM long-term survivors relative to the other groups, since a significant depletion in CIN signature 11 relative to GBM typical survivors was the only alteration detected. In contrast, within IDH-mutant grade 4 astrocytomas we detected a significant enrichment of CIN signature 5 and 10 activities and a depletion of CIN signature 1 activity relative to tumors of GBM typical survivors.ConclusionsOur data suggest that CIN is pervasive in high grade gliomas, however this is unlikely to be a major contributor to the phenomenon of long-term survivorship in GBM. Nevertheless, further evaluation of specific types of CIN (signatures) could have prognostic value in patients suffering from grade 4 gliomas.
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- 2024
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34. Genome instability-related LINC02577, LINC01133 and AC107464.2 are lncRNA prognostic markers correlated with immune microenvironment in pancreatic adenocarcinoma
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Yinjiang Zhang, Yao Wang, Xu He, Rongfei Yao, Lu Fan, Linyi Zhao, Binan Lu, and Zongran Pang
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Pancreatic adenocarcinoma ,Genome instability ,Immune checkpoint ,Immunotherapy ,LncRNA ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Pancreatic adenocarcinoma (PAAD) is a leading cause of malignancy-related deaths worldwide, and the efficacy of immunotherapy on PAAD is limited. Studies report that long non-coding RNAs (lncRNAs) play an important role in modulating genomic instability and immunotherapy. However, the identification of genome instability-related lncRNAs and their clinical significance has not been investigated in PAAD. Methods The current study developed a computational framework for mutation hypothesis based on lncRNA expression profile and somatic mutation spectrum in pancreatic adenocarcinoma genome. We explored the potential of GInLncRNAs(genome instability-related lncRNAs) through co-expression analysis and function enrichment analysis. We further analyzed GInLncRNAs by Cox regression and used the results to construct a prognostic lncRNA signature. Finally, we analyzed the relationship between GILncSig (genomic instability derived 3-lncRNA signature) and immunotherapy. Results A GILncSig was developed using bioinformatics analyses. It could divide patients into high-risk and low-risk groups, and there was a significant difference in OS between the two groups. In addition, GILncSig was associated with genome mutation rate in pancreatic adenocarcinoma, indicating its potential value as a marker for genomic instability. The GILncSig accurately grouped wild type patients of KRAS into two risk groups. The prognosis of the low-risk group was significantly improved. GILncSig was significantly correlated with the level of immune cell infiltration and immune checkpoint. Conclusions In summary, the current study provides a basis for further studies on the role of lncRNA in genomic instability and immunotherapy. The study provides a novel method for identification of cancer biomarkers related to genomic instability and immunotherapy.
- Published
- 2023
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35. SSBlazer: a genome-wide nucleotide-resolution model for predicting single-strand break sites
- Author
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Xu, Sheng, Wei, Junkang, Sun, Siqi, Zhang, Jizhou, Chan, Ting-Fung, and Li, Yu
- Published
- 2024
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36. Unrepaired base excision repair intermediates in template DNA strands trigger replication fork collapse and PARP inhibitor sensitivity.
- Author
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Serrano‐Benitez, Almudena, Wells, Sophie E, Drummond‐Clarke, Lylah, Russo, Lilian C, Thomas, John Christopher, Leal, Giovanna A, Farrow, Mark, Edgerton, James Michael, Balasubramanian, Shankar, Yang, Ming, Frezza, Christian, Gautam, Amit, Brazina, Jan, Burdova, Kamila, Hoch, Nicolas C, Jackson, Stephen P, and Caldecott, Keith W
- Subjects
- *
DNA replication , *SISTER chromatid exchange , *SINGLE-strand DNA breaks , *POLY(ADP-ribose) polymerase , *CHROMOSOME replication , *URIDINE , *DNA - Abstract
DNA single‐strand breaks (SSBs) disrupt DNA replication and induce chromosome breakage. However, whether SSBs induce chromosome breakage when present behind replication forks or ahead of replication forks is unclear. To address this question, we exploited an exquisite sensitivity of SSB repair‐defective human cells lacking PARP activity or XRCC1 to the thymidine analogue 5‐chloro‐2′‐deoxyuridine (CldU). We show that incubation with CldU in these cells results in chromosome breakage, sister chromatid exchange, and cytotoxicity by a mechanism that depends on the S phase activity of uracil DNA glycosylase (UNG). Importantly, we show that CldU incorporation in one cell cycle is cytotoxic only during the following cell cycle, when it is present in template DNA. In agreement with this, while UNG induces SSBs both in nascent strands behind replication forks and in template strands ahead of replication forks, only the latter trigger fork collapse and chromosome breakage. Finally, we show that BRCA‐defective cells are hypersensitive to CldU, either alone and/or in combination with PARP inhibitor, suggesting that CldU may have clinical utility. Synopsis: UNG glycosylase excises genomic chlorouracil from cells treated with 5‐chloro‐2′‐deoxyuridine (CldU), inducing template strand breaks and replication fork collapse. Cells lacking single‐strand break repair or BRCA1/BRCA2 are hypersensitive to CldU, alone and in combination with PARP inhibitor. The DNA glycosylase UNG excises chlorouracil, inducing DNA single‐strand breaks that collapse DNA replication forks.Human cells lacking the single‐strand break repair protein XRCC1 or incubated with PARP inhibitor are exquisitely sensitive to the thymine analogue, 5‐chloro‐2′‐deoxyuridine (CldU).CldU may have clinical utility for BRCA‐defective cancers, alone or in combination with PARP inhibitors. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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37. G1 Dynamics at the Crossroads of Pluripotency and Cancer.
- Author
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Fleifel, Dalia and Cook, Jeanette Gowen
- Subjects
- *
DNA metabolism , *PROTEIN metabolism , *PROTEIN kinases , *GROWTH factors , *CARCINOGENESIS , *CELL cycle , *GENE expression , *TUMORS - Abstract
Simple Summary: The cell division cycle is tightly regulated to ensure faithful and complete DNA replication. A critical cell cycle phase is G1 in which cells prepare DNA for replication in S phase. Interestingly, stem cells and cancer cells have both similarities and differences in their cell cycle regulatory mechanisms. In this review, we address the role of various cell cycle regulators in controlling the dynamics of G1 phase in stem cells and cancer cells. We also discuss recent advances in understanding how core pluripotency factors regulate the cell cycle and play dual roles in stem cell pluripotency and in cancers where they are aberrantly expressed. A better understanding of these common regulatory networks could offer potential new therapeutic avenues for cancer. G1 cell cycle phase dynamics are regulated by intricate networks involving cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors, which control G1 progression and ensure proper cell cycle transitions. Moreover, adequate origin licensing in G1 phase, the first committed step of DNA replication in the subsequent S phase, is essential to maintain genome integrity. In this review, we highlight the intriguing parallels and disparities in G1 dynamics between stem cells and cancer cells, focusing on their regulatory mechanisms and functional outcomes. Notably, SOX2, OCT4, KLF4, and the pluripotency reprogramming facilitator c-MYC, known for their role in establishing and maintaining stem cell pluripotency, are also aberrantly expressed in certain cancer cells. In this review, we discuss recent advances in understanding the regulatory role of these pluripotency factors in G1 dynamics in the context of stem cells and cancer cells, which may offer new insights into the interconnections between pluripotency and tumorigenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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38. Assessment of the genomic stability of calves obtained from artificial insemination and OPU/IVP in vitro fertilization.
- Author
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Kępka, Katarzyna, Wójcik, Ewa, and Wysokińska, Anna
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ARTIFICIAL insemination , *FERTILIZATION in vitro , *SISTER chromatid exchange , *CALVES , *HUMAN in vitro fertilization , *IDENTIFICATION of animals - Abstract
Damage to genetic material and errors in the functioning of cellular mechanisms disturb genome stability and integrity. Assessment of genomic stability in animals is a very important aspect of breeding work. Unfortunately, harmful instabilities affect the functioning, health and reproductive processes of animals. Obtaining healthy calves is a priority, whatever methods of reproductive biotechnology are applied. The aim of the study was to assess the genomic stability of calves obtained from artificial insemination and OPU/IVP in vitro fertilization. The genomic stability of the calves was evaluated using the comet, sister chromatid exchange, and fragile sites assays. Damage to the genetic material of calves obtained by two reproductive biotechnologies was identified. Identification of instability in animals can be a valuable tool in breeding work and accelerate breeding progress. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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39. Dynamics of Amino Acid Metabolism, Gene Expression, and Circulomics in a Recombinant Chinese Hamster Ovary Cell Line Adapted to Moderate and High Levels of Extracellular Lactate.
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Chitwood, Dylan G., Uy, Lisa, Fu, Wanfang, Klaubert, Stephanie R., Harcum, Sarah W., and Saski, Christopher A.
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CHO cell , *AMINO acid metabolism , *LACTATES , *GENE expression , *CELL lines , *EXTRACHROMOSOMAL DNA , *CIRCULAR DNA - Abstract
The accumulation of metabolic wastes in cell cultures can diminish product quality, reduce productivity, and trigger apoptosis. The limitation or removal of unintended waste products from Chinese hamster ovary (CHO) cell cultures has been attempted through multiple process and genetic engineering avenues with varied levels of success. One study demonstrated a simple method to reduce lactate and ammonia production in CHO cells with adaptation to extracellular lactate; however, the mechanism behind adaptation was not certain. To address this profound gap, this study characterizes the phenotype of a recombinant CHO K-1 cell line that was gradually adapted to moderate and high levels of extracellular lactate and examines the genomic content and role of extrachromosomal circular DNA (eccDNA) and gene expression on the adaptation process. More than 500 genes were observed on eccDNAs. Notably, more than 1000 genes were observed to be differentially expressed at different levels of lactate adaptation, while only 137 genes were found to be differentially expressed between unadapted cells and cells adapted to grow in high levels of lactate; this suggests stochastic switching as a potential stress adaptation mechanism in CHO cells. Further, these data suggest alanine biosynthesis as a potential stress-mitigation mechanism for excess lactate in CHO cells. [ABSTRACT FROM AUTHOR]
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- 2023
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40. Plants Stress: Salt Stress and Mechanisms of Stress Tolerance.
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SHARMA, MANOJ KUMAR
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BIOTIC communities ,ABIOTIC stress ,AGRICULTURAL productivity ,SALINITY ,MITOGEN-activated protein kinases ,REACTIVE oxygen species - Abstract
A diverse combination of biotic and abiotic pressures makes up the environment that plants naturally inhabit. These pressures cause similarly complicated responses in plants. The purpose of the review is to critically evaluate the effects of various stress stimuli on higher plants with an emphasis on the typical and distinctive dose-dependent responses that are essential for plant growth and development. In order to improve agricultural productivity, breed new salt-tolerant cultivars, and make the most of saline land, it is essential to comprehend the mechanisms underlying plant salt tolerance. Soil salinization has emerged as a global problem. Locating regulatory centres in complex networks is made possible by systems biology techniques, enabling a multi-targeted approach. The goal of systems biology is to organise the molecular constituents of an organism (transcripts, proteins, and metabolites) into functioning networks or models that describe and forecast the dynamic behaviours of that organism in diverse contexts. This review focuses on the molecular, physiological, and pharmacological mechanisms that underlie how stress affects genomic instability, including DNA damage. Additionally, a summary of the physiological mechanisms behind salt tolerance, including the removal of reactive oxygen species (ROS) and osmotic adjustment, has been provided. The salt overly sensitive (SOS), calcium-dependent protein kinase (CDPK), mitogen-activated protein kinase (MAPKs), and abscisic acid (ABA) pathways are the four main signalling pathways for stress. According to earlier research, salt stress causes harm to plants by inhibiting photosynthesis, upsetting ion homeostasis, and peroxiding membranes. listed a few genes that are sensitive to salt stress and correspond to physiological systems. The review describes the most recent tactics and procedures for boosting salt tolerance in plants. We can make predictions about how plants will behave in the field and better understand how they respond to different levels of stress by understanding both the positive and negative aspects of stress responses, including genomic instability. The new knowledge can be put to use to enhance crop productivity and develop more resilient plant kinds, ensuring a consistent supply of food for the global population, which is currently undergoing rapid expansion. [ABSTRACT FROM AUTHOR]
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- 2023
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41. Landscape of Double-Stranded DNA Breaks in Postmortem Brains from Alzheimer's Disease and Non-Demented Individuals.
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Zhang, Xiaoyu, Liu, Yan, Huang, Ming, Gunewardena, Sumedha, Haeri, Mohammad, Swerdlow, Russell H., and Wang, Ning
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DOUBLE-strand DNA breaks , *ALZHEIMER'S disease , *AUTOPSY , *GENE expression , *SINGLE nucleotide polymorphisms , *EPIGENOMICS - Abstract
Background: Alzheimer's disease (AD) brains accumulate DNA double-strand breaks (DSBs), which could contribute to neurodegeneration and dysfunction. The genomic distribution of AD brain DSBs is unclear. Objective: To map genome-wide DSB distributions in AD and age-matched control brains. Methods: We obtained autopsy brain tissue from 3 AD and 3 age-matched control individuals. The donors were men between the ages of 78 to 91. Nuclei extracted from frontal cortex tissue were subjected to Cleavage Under Targets & Release Using Nuclease (CUT&RUN) assay with an antibody against γH2AX, a marker of DSB formation. γH2AX-enriched chromatins were purified and analyzed via high-throughput genomic sequencing. Results: The AD brains contained 18 times more DSBs than the control brains and the pattern of AD DSBs differed from the control brain pattern. In conjunction with published genome, epigenome, and transcriptome analyses, our data revealed aberrant DSB formation correlates with AD-associated single-nucleotide polymorphisms, increased chromatin accessibility, and upregulated gene expression. Conclusion: Our data suggest in AD, an accumulation of DSBs at ectopic genomic loci could contribute to an aberrant upregulation of gene expression. [ABSTRACT FROM AUTHOR]
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- 2023
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42. Unravelling the Role of PARP1 in Homeostasis and Tumorigenesis: Implications for Anti-Cancer Therapies and Overcoming Resistance.
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Lovsund, Taylor, Mashayekhi, Fatemeh, Fitieh, Amira, Stafford, James, and Ismail, Ismail Hassan
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POLY ADP ribose , *ANTINEOPLASTIC agents , *HOMEOSTASIS , *NEOPLASTIC cell transformation , *DNA repair , *POLY(ADP-ribose) polymerase - Abstract
Detailing the connection between homeostatic functions of enzymatic families and eventual progression into tumorigenesis is crucial to our understanding of anti-cancer therapies. One key enzyme group involved in this process is the Poly (ADP-ribose) polymerase (PARP) family, responsible for an expansive number of cellular functions, featuring members well established as regulators of DNA repair, genomic stability and beyond. Several PARP inhibitors (PARPi) have been approved for clinical use in a range of cancers, with many more still in trials. Unfortunately, the occurrence of resistance to PARPi therapy is growing in prevalence and requires the introduction of novel counter-resistance mechanisms to maintain efficacy. In this review, we summarize the updated understanding of the vast homeostatic functions the PARP family mediates and pin the importance of PARPi therapies as anti-cancer agents while discussing resistance mechanisms and current up-and-coming counter-strategies for countering such resistance. [ABSTRACT FROM AUTHOR]
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- 2023
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43. Disruption of the Mammalian Ccr4–Not Complex Contributes to Transcription-Mediated Genome Instability.
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Hagkarim, Nafiseh Chalabi, Hajkarim, Morteza Chalabi, Suzuki, Toru, Fujiwara, Toshinobu, Winkler, G. Sebastiaan, Stewart, Grant S., and Grand, Roger J.
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RNA synthesis , *GENE expression , *GENOMES , *MITOGEN-activated protein kinases , *RNA regulation , *MITOGENS , *CHROMATIN-remodeling complexes , *DNA replication - Abstract
The mammalian Ccr4–Not complex, carbon catabolite repression 4 (Ccr4)-negative on TATA-less (Not), is a large, highly conserved, multifunctional assembly of proteins that acts at different cellular levels to regulate gene expression. It is involved in the control of the cell cycle, chromatin modification, activation and inhibition of transcription initiation, control of transcription elongation, RNA export, and nuclear RNA surveillance; the Ccr4–Not complex also plays a central role in the regulation of mRNA decay. Growing evidence suggests that gene transcription has a vital role in shaping the landscape of genome replication and is also a potent source of replication stress and genome instability. Here, we have examined the effects of the inactivation of the Ccr4–Not complex, via the depletion of the scaffold subunit CNOT1, on DNA replication and genome integrity in mammalian cells. In CNOT1-depleted cells, the elevated expression of the general transcription factor TATA-box binding protein (TBP) leads to increased RNA synthesis, which, together with R-loop accumulation, results in replication fork slowing, DNA damage, and senescence. Furthermore, we have shown that the stability of TBP mRNA increases in the absence of CNOT1, which may explain its elevated protein expression in CNOT1-depleted cells. Finally, we have shown the activation of mitogen-activated protein kinase signalling as evidenced by ERK1/2 phosphorylation in the absence of CNOT1, which may be responsible for the observed cell cycle arrest at the border of G1/S. [ABSTRACT FROM AUTHOR]
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- 2023
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44. Genome Instability of Hippocampal and Bone Marrow Cells in Male Mice Exposed to Immobilization and Female Pheromone Stressor.
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Shcherbinina, V. D., Bakulevskiy, B. V., Glinin, T. S., and Daev, E. V.
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BONE marrow cells , *HIPPOCAMPUS (Brain) , *GENOMES , *MICE , *DNA damage , *PHEROMONES - Abstract
Different stressors, while affecting the cells of target organs, can lead to genome instability and even disintegration, which can matter in the formation of post-stress disorders. We studied the effect of psycho-emotional stressors (immobilization and the house mouse female pheromone 2,5-dimethylpyrazine) on DNA integrity of hippocampal and bone marrow cells in CD-1, CBA and C3H male mice, using the cytogenetic and immunocytochemical methods (alkaline comet assay, ana-telophase test for mitotic disturbances, γH2AX focus assay). It was shown that both immobilization and 2,5-dimethylpyrazine cause genome damage in the cells of both organs studied. Cell genome destabilization in various organs is considered as an essential stage of stress response development in an attempt of the organism to adapt to extreme environmental exposures. [ABSTRACT FROM AUTHOR]
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- 2023
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45. Pharmacotherapy during pregnancy and its association with genome instability in mother and fetus
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Đorđević Katarina M., Arsenijević Slobodan N., Milošević-Đorđević Olivera M., Marinković Dragoslav M., and Grujičić Darko V.
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pregnancy ,pharmacotherapy ,genome instability ,human peripheral blood lymphocytes ,umbilical blood lymphocytes ,Science - Abstract
Pregnancy is a special physiological condition, where drug treatment presents a special concern. The use of drugs during pregnancy is increasing. Micronuclei, chromosomal aberrations, and sister chromatid exchanges are biomarkers of early biological effects which play an important role in assessing the genetic integrity of both individuals and populations. The aim of this review is to make a cross-section of previously conducted studies on the detections of genotoxic effects of drugs on human peripheral blood lymphocytes, after therapeutic exposure during the second and third trimester of pregnancy, as well as in umbilical blood lymphocytes of newborns whose mothers received the same therapy. Previous studies have shown that the cells of pregnant women and newborns are very sensitive to the effects of genotoxins, and cytogenetic biomarkers are associated with the risk of developing numerous diseases, including cancer in adults. Altogether, the administration of various doses and times of use of medications should be performed with caution.
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- 2023
46. Overexpression of SMYD3 Promotes Autosomal Dominant Polycystic Kidney Disease by Mediating Cell Proliferation and Genome Instability
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Ewud Agborbesong, Julie Xia Zhou, Hongbing Zhang, Linda Xiaoyan Li, Peter C. Harris, James P. Calvet, and Xiaogang Li
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nephrology ,ADPKD ,epigenetics ,SMYD3 ,genome instability ,Biology (General) ,QH301-705.5 - Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder worldwide and progresses to end-stage renal disease (ESRD). However, its precise mechanism is not fully understood. In recent years, epigenetic reprogramming has drawn increasing attention regarding its effect on cyst growth. However, considering the complexity of epigenetic mechanisms and the broad range of alterations of epigenetic components in ADPKD, identifying more specific epigenetic factors and understanding how they are mechanistically linked to promote cyst growth is relevant for the development of treatment for ADPKD. Here, we find that the histone methyltransferase SMYD3, which activates gene transcription via histone H3 lysine 4 trimethylation (H3K4me3), is upregulated in PKD1 mutant mouse and human ADPKD kidneys. Genetic knockout of SMYD3 in a PKD1 knockout mouse model delayed cyst growth and improved kidney function compared with PKD1 single knockout mouse kidneys. Immunostaining and Western blot assays indicated that SMYD3 regulated PKD1-associated signaling pathways associated with proliferation, apoptosis, and cell cycle effectors in PKD1 mutant renal epithelial cells and tissues. In addition, we found that SMYD3 localized to the centrosome and regulated mitosis and cytokinesis via methylation of α-tubulin at lysine 40. In addition, SMYD3 regulated primary cilia assembly in PKD1 mutant mouse kidneys. In summary, our results demonstrate that overexpression of SMYD3 contributes to cyst progression and suggests targeting SMYD3 as a potential therapeutic strategy for ADPKD.
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- 2024
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47. Genome instability-derived genes as a novel prognostic signature for lung adenocarcinoma
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Xu Zhang, Tak-Wah Lam, and Hing-Fung Ting
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genome instability ,lung adenocarcinoma ,somatic mutations ,copy number variation ,fusion genes ,overall survival prediction ,Biology (General) ,QH301-705.5 - Abstract
Background: An increasing number of patients are being diagnosed with lung adenocarcinoma, but there remains limited progress in enhancing prognostic outcomes and improving survival rates for these patients. Genome instability is considered a contributing factor, as it enables other hallmarks of cancer to acquire functional capabilities, thus allowing cancer cells to survive, proliferate, and disseminate. Despite the importance of genome instability in cancer development, few studies have explored the prognostic signature associated with genome instability for lung adenocarcinoma.Methods: In the study, we randomly divided 397 lung adenocarcinoma patients from The Cancer Genome Atlas database into a training group (n = 199) and a testing group (n = 198). By calculating the cumulative counts of genomic alterations for each patient in the training group, we distinguished the top 25% and bottom 25% of patients. We then compared their gene expressions to identify genome instability-related genes. Next, we used univariate and multivariate Cox regression analyses to identify the prognostic signature. We also performed the Kaplan–Meier survival analysis and the log-rank test to evaluate the performance of the identified prognostic signature. The performance of the signature was further validated in the testing group, in The Cancer Genome Atlas dataset, and in external datasets. We also conducted a time-dependent receiver operating characteristic analysis to compare our signature with established prognostic signatures to demonstrate its potential clinical value.Results: We identified GULPsig, which includes IGF2BP1, IGF2BP3, SMC1B, CLDN6, and LY6K, as a prognostic signature for lung adenocarcinoma patients from 42 genome instability-related genes. Based on the risk score of the risk model with GULPsig, we successfully stratified the patients into high- and low-risk groups according to the results of the Kaplan–Meier survival analysis and the log-rank test. We further validated the performance of GULPsig as an independent prognostic signature and observed that it outperformed established prognostic signatures.Conclusion: We provided new insights to explore the clinical application of genome instability and identified GULPsig as a potential prognostic signature for lung adenocarcinoma patients.
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- 2023
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48. A pathogenic variant in the uncharacterized RNF212B gene results in severe aneuploidy male infertility and repeated IVF failure
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Moran Gershoni, Tslil Braun, Ron Hauser, Shimi Barda, Ofer Lehavi, Mira Malcov, Tsvia Frumkin, Yael Kalma, Shmuel Pietrokovski, Eli Arama, and Sandra E. Kleiman
- Subjects
Aneuploidy ,IVF failures ,Human infertility ,RNF212B ,Meiosis ,Genome instability ,Genetics ,QH426-470 - Abstract
Summary: Quantitative and qualitative spermatogenic impairments are major causes of men’s infertility. Although in vitro fertilization (IVF) is effective, some couples persistently fail to conceive. To identify causal variants in patients with severe male infertility factor and repeated IVF failures, we sequenced the exome of two consanguineous family members who underwent several failed IVF cycles and were diagnosed with low sperm count and motility. We identified a rare homozygous nonsense mutation in a previously uncharacterized gene, RNF212B, as the causative variant. Recurrence was identified in another unrelated, infertile patient who also faced repeated failed IVF treatments. scRNA-seq demonstrated meiosis-specific expression of RNF212B. Sequence analysis located a protein domain known to be associated with aneuploidy, which can explain multiple IVF failures. Accordingly, FISH analysis revealed a high aneuploidy rate in the patients' sperm cells and their IVF embryos. Finally, inactivation of the Drosophila orthologs significantly reduced male fertility. Given that members of the evolutionary conserved RNF212 gene family are involved in meiotic recombination and crossover maturation, our findings indicate a critical role of RNF212B in meiosis, genome stability, and in human fertility. Since recombination is completely absent in Drosophila males, our findings may indicate an additional unrelated role for the RNF212-like paralogs in spermatogenesis.
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- 2023
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- View/download PDF
49. Three recent sex chromosome-to-autosome fusions in a Drosophila virilis strain with high satellite DNA content.
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Flynn, Jullien M., Hu, Kevin B., and Clark, Andrew G.
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DNA , *GENETIC mutation , *KARYOTYPES , *SEX chromosome abnormalities , *RESEARCH funding , *INSECTS , *DNA damage - Abstract
The karyotype, or number and arrangement of chromosomes, has varying levels of stability across both evolution and disease. Karyotype changes often originate from DNA breaks near the centromeres of chromosomes, which generally contain long arrays of tandem repeats or satellite DNA. Drosophila virilis possesses among the highest relative satellite abundances of studied species, with almost half its genome composed of three related 7 bp satellites. We discovered a strain of D. virilis that we infer recently underwent three independent chromosome fusion events involving the X and Y chromosomes, in addition to one subsequent fission event. Here, we isolate and characterize the four different karyotypes we discovered in this strain which we believe demonstrates remarkable genome instability. We discovered that one of the substrains with an X-autosome fusion has an X-to-Y chromosome nondisjunction rate 20 × higher than the D. virilis reference strain (21% vs 1%). Finally, we found an overall higher rate of DNA breakage in the substrain with higher satellite DNA compared to a genetically similar substrain with less satellite DNA. This suggests that satellite DNA abundance may play a role in the risk of genome instability. Overall, we introduce a novel system consisting of a single strain with four different karyotypes, which we believe will be useful for future studies of genome instability, centromere function, and sex chromosome evolution. Keywords: Robertsonian. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
50. POT1 mutations cause differential effects on telomere length leading to opposing disease phenotypes.
- Author
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Zade, Nikita Harish and Khattar, Ekta
- Subjects
- *
TELOMERES , *CELLULAR aging , *DNA repair , *PHENOTYPES - Abstract
The protection of telomere protein (POT1) is a telomere‐binding protein and is an essential component of the six‐membered shelterin complex, which is associated with the telomeres. POT1 directly binds to the 3′ single‐stranded telomeric overhang and prevents the activation of DNA damage response at telomeres thus preventing the telomere–telomere fusions and genomic instability. POT1 also plays a pivotal role in maintaining telomere length by regulating telomerase‐mediated telomere elongation. Mutations in POT1 proteins result in three different telomere phenotypes, which include long, short, or aberrant telomere length. Long telomeres predispose individuals to cancer, while short or aberrant telomere phenotypes result in pro‐aging diseases referred to as telomeropathies. Here, we review the function of POT1 proteins in telomere length hemostasis and how the spectrum of mutations reported in POT1 can be segregated toward developing very distinct disease phenotypes of cancer and telomeropathies. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
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