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The incidence of cancer globally is increasing, partly due to lifestyle factors. Despite a better understanding of cancer biology and advancement in cancer management and therapies, current strategies in cancer treatment remain costly and cause socioeconomic burden especially in Asian countries. Hence, instead of putting more efforts in searches for new cancer cures, attention has now shifted to understanding how to mitigate cancer risk by modulating lifestyle factors. It has been established that carcinogenesis is multifactorial, and the important detrimental role of oxidative stress, chronic inflammation, and genomic instability is evident. To date, there is no study linking dietary pattern and genomic stability in cancer risk in the Asian food landscape. Thus, this present review article discusses recent literature on dietary pattern and genomic stability and its relationship with cancer risk in Asia.

Neurodegeneration is a complex neurological phenomenon characterized by disturbed coherence in neuronal efflux. Progressive neuronal loss and brain damage due to various age-related pathological hallmarks perturb the behavioral balance and quality of life. Sirtuins have been widely investigated for their neuroprotective role, with SIRT1 being the most contemplated member of the family. SIRT1 exhibits significant capabilities to enhance neurogenesis and cellular lifespan by regulating various pathways, which makes it an exciting therapeutic target to inhibit neurodegenerative disease progression. SIRT1 mediated neuronal fortification involves modulation of molecular co-factors and biochemical pathways responsible for the induction and sustenance of pro-inflammatory and pro-oxidative environment in the cellular milieu. In this review, we present the major role played by SIRT1 in maintaining cellular strength through the regulation of genomic stability, neuronal growth, energy metabolism, oxidative stress, inhibiting mechanisms and anti-inflammatory responses. The therapeutic significance of SIRT1 has been put into perspective through a comprehensive discussion about its ameliorating potential against neurodegenerative stimuli in a variety of diseases that characteristically impair cognition, memory and motor coordination. This review enhances the acquaintance concerned with the neuroprotective potential of SIRT1 and thus promotes the development of novel SIRT1 regulating therapeutic agents and strategies.

In this study, arsenic (As)-induced genotoxicity in the roots and shoots of Cucumis melo (melon) seedlings were investigated by using the random amplified polymorphic DNA - polymerase chain reaction (RAPD-PCR) and comet assays. For this purpose, melon seedlings were exposed to arsenate [As(V)] at 0, 100, 200, 300, and 400 μM concentrations in the hydroponic system for 14 days to examine the level of As accumulation, alterations in growth parameters, and DNA damage. A reduction in growth with increasing As(V) concentration was observed in the melon seedlings. Total As accumulations in the shoot and root tissue increased in a dose-dependent manner; however, the level was higher in the roots than the shoots. In RAPD-PCR analysis, 26 primers gave reproducible and scorable results and produced a total of 128 bands in the control seedlings. Alterations in RAPD profiles, including the loss or appearance of new bands, were determined in the As-treated seedlings when compared to the control. The values of genomic template stability (GTS) were decreased by increasing the concentration of the As(V) in both tissue types. DNA strand breaks were observed in all the tested As(V) concentrations in the alkaline comet assay; furthermore, the loss of DNA integrity was higher with 300 and 400 μM As(V) treatments. The results clearly indicate that the combination of DNA-based molecular and cytogenetic techniques (e.g. the comet assay) may be proposed as a reliable evaluation of genotoxicity in plants after exposure to heavy metal pollution.

Sumoylation is an essential post-translational modification intimately involved in a diverse range of eukaryotic cellular mechanisms. Small ubiquitin-like modifier (SUMO) protein isoforms can be reversibly linked to lysine residues that reside within specific motifs on thousands of target substrates, leading to modulations in stability, solubility, localization, and interactor profile. Since its initial discovery almost 25 years ago, SUMO has been described as a key regulator of genomic stability, cell proliferation, and infection among other processes. In this review, we trace the exciting developments in the history of this critical modifier, highlighting SUMO's roles in pathogenesis as well as its potential for the development of targeted therapies for numerous diseases.

BRCA2 is a key breast cancer associated protein that is predicted to have interspersed regions of intrinsic disorder. Intrinsic disorder coupled with large size likely allows BRCA2 to sample a broad range of conformational space. We expect that the resulting dynamic arrangements of BRCA2 domains are a functionally important aspect of its role in homologous recombination DNA repair. To determine the architectural organization and the associated conformational landscape of BRCA2, we used scanning force microscopy based single molecule analyses to map the flexible regions of the protein and characterize which regions influence oligomerization. We show that the N- and the C-terminal regions are the main flexible regions. Both of these regions also influence BRCA2 oligomerization and interaction with RAD51. In the central Brc repeat region, Brc 1–4 and Brc 5–8 contribute synergistically to BRCA2 interaction with RAD51. We also analysed several single amino acid changes that are potentially clinically relevant and found one, the variant of F1524V, which disrupts key interactions and alters the conformational landscape of the protein. We describe the overall conformation spectrum of BRCA2, which suggests that dynamic structural transitions are key features of its biological function, maintaining genomic stability.

Fanconi anemia is a genetically and phenotypically heterogenous disorder characterized by DNA repair deficiency and telomeric erosion. Different antioxidants have been assessed to regain the chromosomal stability in Fanconi anemia, among those is the Resveratrol. In Vitro Micronucleus assay provides a convenient and reliable index of both chromosome breakage and chromosome loss assessment. This study aims to assess the effect of Resveratrol on the stability of the chromosomes in Fanconi anemia patients using in vitro micronucleus assay as a parameter of improvement. The present study was conducted on 10 patients and 10 normal controls matching in age and sex. Induction of breakage by 1,3-Butadiene diepoxide and evaluation of the antioxidant effect of Resveratrol on genomic stability using In Vitro Micronucleus assay technique were done. Significant reduction in the level of micronuclei in cultures treated with Resveratrol was found. Resveratrol could be an effective adjuvant therapy for patients with FA to improve their hematological condition, chromosomal stability and it might protect from cancer development.

Glioblastoma (GBM) is the most aggressive and common type of adult malignant brain tumor, with a median survival of only 21 months. To identify which genes drive its highly aggressive phenotype, we performed a genome-wide CRISPR-Cas9 knockout screen. Results showed substantial enrichment of ~160 novel essential oncogenic driver genes and pathways, including a previously unstudied gene THOC1—involved in RNA processing—that showed significant elevations in expression at RNA and protein levels (p< 0.05) in GBM, as well as a significant survival benefit in patient datasets when downregulated (p< 0.05). Knocking out THOC1 resulted in cell death in multiple GBM patient-derived xenograft (PDX) lines and extended survival compared to the controls (p< 0.01) in vivo. Overexpression of THOC1 in neural stem cells resulted in transformation to a cancerous phenotype, as evidenced by sphere formation in a soft agar assay (p< 0.01) and in vivo tumor engraftment assays. Further investigation of THOC1 through immunoprecipitation in neural stem cells and multiple GBM lines showed significant interaction in GBM with histone deacetylase complex SIN3A, involved in recruiting major histone deacetylases in order to close the DNA and prevent the accumulation of R-loops, RNA:DNA hybrids that pose a threat to genomic stability. Additional investigation revealed that THOC1-knockdowns in vitro induced R-loop formation and DNA damage, while THOC1-overexpression in vitro resulted in an untenable decrease in R-loops and DNA damage, suggesting that the THOC1-SIN3A axis is elevated in GBM in order to prevent the accumulation of genotoxic R-loops. Additionally, histone deacetylase activity was shown to be elevated in THOC1-overexpression conditions and reduced in THOC1-knockdown conditions, confirming that the THOC1-SIN3A axis functions to prevent R-loop accumulation through the epigenetic regulation. In summary, our whole-genome CRISPR-Cas9 knockout screen has identified a promising therapeutic target for GBM—a disease desperately in need of therapeutic innovations.

Breast Cancer gene 1 (BRCA1) is a large, multi-functional protein that regulates a variety of mechanisms in multiple different tissues. Our work established that Brca1 is expressed in skeletal muscle and localizes to the mitochondria and nucleus. Here, we propose BRCA1 expression is critical for the maintenance of force production and mitochondrial respiration in skeletal muscle.

Protection of genome integrity is vital for all living organisms, particularly when DNA double-strand breaks (DSBs) occur. Eukaryotes have developed two main pathways, namely Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR), to repair DSBs. While most of the current research is focused on the role of key protein players in the functional regulation of DSB repair pathways, accumulating evidence has uncovered a novel class of regulating factors termed non-coding RNAs. Non-coding RNAs have been found to hold a pivotal role in the activation of DSB repair mechanisms, thereby safeguarding genomic stability. In particular, long non-coding RNAs (lncRNAs) have begun to emerge as new players with vast therapeutic potential. This review summarizes important advances in the field of lncRNAs, including characterization of recently identified lncRNAs, and their implication in DSB repair pathways in the context of tumorigenesis.

Pluripotent stem cells (PSCs) are capable of generating all types of cells in the body and have promising applications in basic research and cell-based regenerative medicine. Compared to the differentiated cells, PSCs are superior in maintaining genomic stability. However, the underlying molecular mechanisms are far from clear. Here, we summarized the understandings on the molecules and pathways that PSCs specifically utilize to cope with DNA replication-associated stress, to repair DNA damages and to determine cell fates.

Triple‐negative breast cancer (TNBC) is a malignancy that currently lacks targeted therapies. The majority of TNBCs can be characterized as basal‐like and has an expression profile enriched with genes involved in DNA damage repair and checkpoint response. Here, we report that TNBC cells are under replication stress and are constantly generating DNA double‐strand breaks, which is not seen in non‐TNBC cells. Consequently, we found that RECQL5, which encodes a RecQ family DNA helicase involved in many aspects of DNA metabolism including replication and repair, was essential for TNBC cells to survive and proliferate in vitro and in vivo. Compromising RECQL5 function in TNBC cells results in persistence of DNA damage, G2 arrest, and ultimately, cessation of proliferation. Our results suggest RECQL5 may be a potential therapeutic target for TNBC.

DNA damage seriously threats the genomic stability and is linked to mutagenesis, carcinogenesis, and cell death. DNA damage includes the isolated damage and the clustered damages, but few approaches are available for efficient detection of the clustered damage due to its spatial distribution. Herein, we present a single-molecule counting approach with the capability of detecting both the isolated and the clustered damages in genomic DNAs. We employed the repair enzymes to remove the DNA damage and used the terminal deoxynucleotidyl transferase (TdT) to incorporate biotinylated nucleotides and fluorescent nucleotides into the damage sites in a template-independent manner. The number of total oxidative damaged bases is quantified to be 7328-7406 in a single HeLa cell treated with 150 μM H

Poly(ADP-ribosyl)ation (PARylation) is a reversible post-translational modification regulating various biological pathways including DNA damage repair (DDR). Rapid turnover of PARylation is critically important for an optimal DNA damage response and maintaining genomic stability. Recent studies show that PARylation is tightly regulated by a group of enzymes that can erase the ADP-ribose (ADPR) groups from target proteins. The aim of this review is to present a comprehensive understanding of dePARylation enzymes, their substrates and roles in DDR. Special attention will be laid on the role of these proteins in the development of cancer and their feasibility in anticancer therapeutics.

The aim of the present work was to determine proliferation capacity, immunophenotype and genome integrity of mesenchymal stromal cells (MSCs) from horse umbilical cord blood (UCB) at passage stage 5 and 10. Passage 4 cryopreserved UCB-MSCs from six unrelated donors were evaluated. Immunophenotypic analysis of UCB-MSC revealed a cell identity consistent with equine MSC phenotype by high expression of CD90, CD44, CD29, and very low expression of CD4, CD11a/18, CD73, and MHC class I and II antigens. Proliferative differences were noted among the UCB-MSC cultures. UCB-MSCs karyotype characteristics at passage 5 (eg, 2n = 64; XY, or XX) included 20% polyploidy and 62% aneuploidy. At passage 10, the proportion of polyploidy and aneuploidy was 21% and 82%, respectively, with the increase in aneuploidy being significant compared with passage 5. Furthermore, conventional GTG-banded karyotyping revealed several structural chromosome abnormalities at both passage 5 and 10. The clinical relevance of such chromosome instability is unknown, but determination of MSC cytogenetic status and monitoring of patient response to MSC therapies would help address this question.

Proper functioning of cells—their ability to divide, differentiate, and regenerate—is dictated by genomic stability. The main factors contributing to this stability are the telomeric ends that cap chromosomes. Telomere biology and telomerase activity have been of interest to scientists in various medical science fields for years, including the study of both cancer and of senescence and aging. All these processes are accompanied by telomere-length modulation. Maintaining the key levels of telomerase component (hTERT) expression and telomerase activity that provide optimal telomere length as well as some nontelomeric functions represents a promising step in advanced anti-aging strategies, especially in dermocosmetics. Some known naturally derived compounds contribute significantly to telomere and telomerase metabolism. However, before they can be safely used, it is necessary to assess their mechanisms of action and potential side effects. This paper focuses on the metabolic potential of natural compounds to modulate telomerase and telomere biology and thus prevent senescence and skin aging.

DNA replication is a fundamental process of life. Any perturbation of this process by endogenous or exogenous factors impacts on genomic stability and thereby on carcinogenesis. More recently, the replication machinery has been discovered as an interesting target for cancer therapeutic strategies. Given its high biological and clinical relevance, technologies for the analysis of DNA replication have attracted major attention. The so-called DNA fiber spreading technique is a powerful tool to directly monitor various aspects of the replication process by sequential incorporation of halogenated nucleotide analogs which later can be fluorescently stained and analyzed. This chapter outlines the use of the DNA fiber spreading technique for the analysis of replication dynamics and replication structures.

Endocrine-driven malignancies, including breast and prostate cancer, are among the most common human cancers. The relationship between sex steroid hormones (eg, androgen, estrogen, and progesterone), their cognate receptors, and genomic stability lie at the center of endocrine-driven cancer development, progression, and therapeutic resistance. A variety of direct and indirect mechanisms have been described that link steroid hormone signaling to the loss of genomic integrity that drives early carcinogenesis. These effects are often enriched within endocrine receptor cistromes, accounting for the high proportion of mutations and rearrangements in the region of hormone response elements. In other cases, the effects are generalized and rely on a complex array of genetic, epigenetic, and metabolic interactions. Both androgen and estrogen receptors directly modulate the DNA damage response by trans-activating DNA damage response genes and redirecting the cellular repair machinery in the wake of genotoxic stress. Here we review the key mechanistic underpinnings of the relationship between sex steroid hormone receptors and genomic stability. In addition, we summarize emerging research in this area and discuss important implications for cancer prevention and treatment.

The mouse mahoganoid mutation abrogating Mahogunin Ring Finger-1 (MGRN1) E3 ubiquitin ligase expression causes hyperpigmentation, congenital heart defects and neurodegeneration. To study the pathophysiology of MGRN1 loss, we compared Mgrn1-knockout melanocytes with genetically matched controls and melan-md1 (mahoganoid) melanocytes. MGRN1 knockout induced a more differentiated and adherent phenotype, decreased motility, increased the percentage of cells in the S phase of the cell cycle and promoted genomic instability, as shown by stronger &gamma, H2AX labelling, increased burden of DNA breaks and higher abundance of aneuploid cells. Lack of MGRN1 expression decreased the ability of melanocytes to cope with DNA breaks generated by oxidizing agents or hydroxyurea-induced replicative stress, suggesting a contribution of genomic instability to the mahoganoid phenotype. MGRN1 knockout in B16-F10 melanoma cells also augmented pigmentation, increased cell adhesion to collagen, impaired 2D and 3D motility and caused genomic instability. Tumors formed by Mgrn1-KO B16-F10 cells had lower mitotic indices, fewer Ki67-positive cells and showed a trend towards smaller size. In short-term lung colonization assays Mgrn1-KO cells showed impaired colonization potential. Moreover, lower expression of MGRN1 is significantly associated with better survival of human melanoma patients. Therefore, MGRN1 might be an important phenotypic determinant of melanoma cells.

Breast cancer is the most common cancer in women, accounting for approximately 25% of all cancer cases worldwide. Some breast cancer patients are genetically predisposed to genes involved in genomic stability. We report the targeted genome sequencing data of 24 young women (aged below 45 years) breast cancer patients admitted to Cipto Mangunkusumo National Hospital, Jakarta, Indonesia. These data will be useful in detecting the genome markers of breast cancer and in deciding the diagnostics and therapies. DNA sequences were obtained using the Illumina NextSeq 500 platform. FASTQ raw files are available under BioProject accession number PRJNA606794 and Sequence Read Archive accession numbers SRR11774092–SRR11774115.

Ataxia with oculomotor apraxia type 2 (AOA2) is a slowly progressive, autosomal recessive disease characterized by the triad of ataxia, oculomotor apraxia, and sensorimotor neuropathy. The genetic basis of AOA2 is biallelic mutation of the SETX gene, resulting in reduced or absent senataxin, a DNA/RNA repair protein essential for genomic stability.In this case report, we described a case of AOA2 with two clear pathogenic SETX mutations, one of which is novel. We then discussed two further likely “in cis” SETX sequence changes (previously reported in the literature as pathogenic), and presented the case that they are likely benign polymorphisms.

Genomic perturbations due to inaccurate DNA replication, including inappropriate chromosomal segregation often underlie the development of cancer and neurodegenerative diseases. The incidence of these two diseases increases with age and exhibits an inverse association. Therefore, elderly subjects with cancer exhibit a reduced risk of a neurodegenerative disease, and vice versa. Both of these diseases are associated with aging and share several risk factors. Cells have multiple mechanisms to repair DNA damage and inaccurate replication. Previous studies have demonstrated that tumor suppressor proteins serve a critical role in the DNA damage response, which may result in genomic instability and thus induction of cellular apoptosis. Tumor suppressor genes, such as phosphatase and tensin homologue deleted on chromosome 10 (PTEN), breast cancer susceptibility gene 1 (BRCA1) and TP53 reduce genomic susceptibility to cancer by repairing the damaged DNA. In addition, these genes work cooperatively to ensure the inhibition of the development of several types of cancer. PTEN, BRCA1 and TP53 have been recognized as the most frequently deleted and/or mutated genes in various types of human cancer. Recently, tumor suppressor genes have also been shown to be involved in the development of neurodegenerative diseases. The present review summarizes the recent findings of the functions of these tumor suppressors that are associated with genomic stability, and are involved in carcinogenic and neurodegenerative cell signaling. A summary is presented regarding the interactions of these tumor suppressors with their partners which results in transduction of downstream signals. The implications of these functions for cancer and neurodegenerative disease-associated biology are also highlighted.

RECQ1 (also known as RECQL or RECQL1) belongs to the RecQ family of DNA helicases, members of which are linked with rare genetic diseases of cancer predisposition in humans. RECQ1 is implicated in several cellular processes, including DNA repair, cell cycle and growth, telomere maintenance, and transcription. Earlier studies have demonstrated a unique requirement of RECQ1 in ensuring chromosomal stability and suggested its potential involvement in tumorigenesis. Recent reports have suggested that RECQ1 is a potential breast cancer susceptibility gene, and missense mutations in this gene contribute to familial breast cancer development. Here, we provide a framework for understanding how the genetic or functional loss of RECQ1 might contribute to genomic instability and cancer.

Several studies show that triple-negative breast cancer (TNBC) patients have the lowest vitamin D concentration among all breast cancer types, suggesting that this vitamin may induce a protective effect against TNBC. This effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D), can be attributed to its potential to modulate proliferation, differentiation, apoptosis, inflammation, angiogenesis, invasion and metastasis and is supported by many in vitro and animal studies, but its exact mechanism is poorly known. In a fraction of TNBCs that harbor mutations that cause the loss of function of the DNA repair-associated breast cancer type 1 susceptibility (BRCA1) gene, 1,25(OH)2D may induce protective effects by activating its receptor and inactivating cathepsin L-mediated degradation of tumor protein P53 binding protein 1 (TP53BP1), preventing deficiency in DNA double-strand break repair and contributing to genome stability. Similar effects can be induced by the interaction of 1,25(OH)2D with proteins of the growth arrest and DNA damage-inducible 45 (GADD45) family. Further studies on TNBC cell lines with exact molecular characteristics and clinical trials with well-defined cases are needed to determine the mechanism of action of vitamin D in TNBC to assess its preventive and therapeutic potential.

The toxicity of the copper oxide nanoparticles (CuO NP) has been attributed to the so-called &ldquo, Trojan horse&rdquo, type mechanism, relying on the particle uptake and extensive intracellular release of copper ions, due to acidic pH in the lysosomes. Nevertheless, a clear distinction between extra- and intracellular-mediated effects is still missing. Therefore, the impact of the endocytosis inhibitor hydroxy-dynasore (OH-dyn), as well as bafilomycin A1 (bafA1), inhibiting the vacuolar type H+-ATPase (V-ATPase), on the cellular toxicity of nano- and microsized CuO particles, was investigated in BEAS 2 B cells. Selected endpoints were cytotoxicity, copper uptake, glutathione (GSH) levels, and the transcriptional DNA damage and (oxidative) stress response using the high-throughput reverse transcription quantitative polymerase chain reaction (RT-qPCR). OH-dyn markedly reduced intracellular copper accumulation in the cases of CuO NP and CuO MP, the modulation of gene expression, induced by both particle types affecting especially HMOX1, HSPA1A, MT1X, SCL30A1, IL8 and GADD45A, were completely abolished. BafA1 lowered the intracellular copper concentration in case of CuO NP and strongly reduced transcriptional changes, while any CuO MP-mediated effects were not affected by bafA1. In conclusion, the toxicity of CuO NP depended almost exclusively upon dynamin-dependent endocytosis and the intracellular release of redox-active copper ions due to lysosomal acidification, while particle interactions with cellular membranes appeared to be not relevant.

Fondazione Italiana per la Ricerca sul Cancro FIRC 18112 Sina Atashpaz.Fondazione Umberto Veronesi Sina Atashpaz Associazione Italiana per la Ricerca sul Cancro AIRC 5xmille METAMECH program Vincenzo Costanzo Giovanni Armenise-Harvard Foundation Vincenzo Costanzo European Research Council Consolidator grant 614541 Vincenzo Costanzo Associazione Italiana per la Ricerca sul Cancro Fellowship 23961 Negar ArghavanifarDanish Cancer Society KBVU-2014 Andres Joaquin Lopez-Contreras Danish Council for Independent Research Sapere Aude, DFF Starting Grant 2014 Andres Joaquin Lopez-Contreras European Research Council ERC-2015-STG-679068 Andres Joaquin Lopez-Contreras Danish National Research Foundation DNRF115 Andres Joaquin Lopez-Contreras The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Unrepaired DNA damage during embryonic development can be potentially inherited by a large population of cells. However, the quality control mechanisms that minimize the contribution of damaged cells to developing embryos remain poorly understood. Here, we uncovered an ATR- and CHK1-mediated transcriptional response to replication stress (RS) in mouse embryonic stem cells (ESCs) that induces genes expressed in totipotent two-cell (2C) stage embryos and 2C-like cells. This response is mediated by Dux, a multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals. In response to RS, DUX triggers the transcription of 2C-like markers such as murine endogenous retrovirus-like elements (MERVL) and Zscan4. This response can also be elicited by ETAA1-mediated ATR activation in the absence of RS. ATR-mediated activation of DUX requires GRSF1-dependent post-transcriptional regulation of Dux mRNA. Strikingly, activation of ATR expands ESCs fate potential by extending their contribution to both embryonic and extra-embryonic tissues. These findings define a novel ATR dependent pathway involved in maintaining genome stability in developing embryos by controlling ESCs fate in response to RS. Sí

Pluripotent stem cell (PSC) cultures are subjected to selective pressures that can result in acquisition and expansion of recurrent genetic abnormalities at any time. These recurrent abnormalities enhance the variant cells harboring them with a competitive advantage over wild-type cells. Variant cells can eventually supplant wild-type cells entirely and become fixed in culture. Such variants can impact the efficacy of PSCs in research and clinical applications. Therefore, routine genomic characterization is required for reliable and effective use of PSCs. In this article we describe the capabilities and limitations of several assays commonly used for assessing PSC genomic stability. Based on this analysis, we provide a recommendation for integrating assays into a comprehensive testing regimen that maximizes coverage while minimizing cost. © 2020 by John Wiley & Sons, Inc.

Protein phosphatase 4 (PP4), one of serine/threonine phosphatases, is involved in many critical cellular pathways, including DNA damage response (DNA repair, cell cycle regulation, and apoptosis), tumorigenesis, cell migration, immune response, stem cell development, glucose metabolism, and diabetes. PP4 has been steadily studied over the past decade about wide spectrum of physiological activities in cells. Given the many vital functions in cells, PP4 has great potential to develop into the finding of key working mechanisms and effective treatments for related diseases such as cancer and diabetes. In this review, we provide an overview of the cellular and molecular mechanisms by which PP4 impacts and also discuss the functional significance of it in cell health. [BMB Reports 2020; 53(4): 181-190].

Golgi phosphoprotein 3 (GOLPH3), a Phosphatidylinositol 4-Phosphate [PI(4)P] effector at the Golgi, is required for Golgi ribbon structure maintenance, vesicle trafficking and Golgi glycosylation. GOLPH3 has been validated as an oncoprotein through combining integrative genomics with clinopathological and functional analyses. It is frequently amplified in several solid tumor types including melanoma, lung cancer, breast cancer, glioma, and colorectal cancer. Overexpression of GOLPH3 correlates with poor prognosis in multiple tumor types including 52% of breast cancers and 41% to 53% of glioblastoma. Roles of GOLPH3 in tumorigenesis may correlate with several cellular activities including: (i) regulating Golgi-to-plasma membrane trafficking and contributing to malignant secretory phenotypes; (ii) controlling the internalization and recycling of key signaling molecules or increasing the glycosylation of cancer relevant glycoproteins; and (iii) influencing the DNA damage response and maintenance of genomic stability. Here we summarize current knowledge on the oncogenic pathways involving GOLPH3 in human cancer, GOLPH3 influence on tumor metabolism and surrounding stroma, and its possible role in tumor metastasis formation.

Objective: Telomeres are specialized nucleoprotein structures located at the ends of chromosomes, which play a crucial role in genomic stability. Telomere shortening has been proposed as a ...

Background Nijmegen breakage syndrome 1 (NBS1), as a key protein in the DNA double-strand breaks (DSBs) repair pathway, plays an important role in maintaining genomic stability. Although single nucleotide polymorphisms (SNPs) in NBS1 have frequently been studied in multiple cancers, the relationships of two functional NBS1 polymorphisms (rs2735383 and rs1805794) with laryngeal carcinoma are yet unclear. Therefore, in the present study, we performed a case-control study including 342 cases and 345 controls to analyze the associations between two polymorphisms of NBS1 and the risk of laryngeal carcinoma. Methods We used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to determine the genotypes of the functional SNPs in NBS1 gene. Results In comparison with the homozygous rs2735383GG genotype, the CC genotype was significantly associated with an increased risk of laryngeal carcinoma (adjusted OR = 1.884, 95%CI = 1.215–2.921). The rs2735383C variant genotypes (GC + CC) conferred a 1.410-fold increased risk of laryngeal carcinoma (adjusted OR = 1.410, 95%CI = 1.004–1.980). Furthermore, when compared to rs2735383GG genotype in laryngeal carcinoma tissues, the combined GC and CC genotypes exerted a significantly lower mRNA level of NBS1 (P = 0.003). In contrast, no significant association was found between rs1805794G > C polymorphism and cancer risk (adjusted OR = 1.074, 95%CI = 0.759–1.518 for GC; adjusted OR = 1.100, 95%CI = 0.678–1.787 for CC; adjusted OR = 1.079, 95%CI = 0.774–1.505 for GC + CC). Conclusions These findings indicate that rs2735383G > C polymorphism in NBS1 may play a crucial role in the development of laryngeal carcinoma. Electronic supplementary material The online version of this article (10.1186/s12885-018-4078-2) contains supplementary material, which is available to authorized users.

Objectives: to evaluate the neuropsychomotor development and the genomic stability associated to folate and blood iron levels in preschool children. Methods: a cross-sectional study in which evaluated the biochemical exams (complete hemogram, serum ferritin, iron and folate), neuropsychomotor development (Denver II Test) and genotoxicity (micronuclei cytome in buccal mucosa cells) of 55 children aging 36-59 months old. Student´s T test, Kruskal-Wallis and Pearson's or Spearman's correlation tests were applied with a significance level of p

Pulmonary vascular remodeling, including proliferation and migration of pulmonary artery endothelial cells (PAEC), is a pathologic hallmark of pulmonary arterial hypertension (PAH). Multiple studies have shown evidence of increased levels of DNA damage and lineage-specific genetic changes in PAH lung vascular cells, suggesting increased genomic instability. Highly proliferative endothelial colony-forming cell (ECFC) clones can be isolated from PAEC. Here we utilized ECFC to track chromosomal copy number of 20 PAH and eight control clones across serial passages using genome-wide microarrays. All PAH clones were genomically stable for at least 20-22 population doublings. At very late passages, ECFC developed a highly aneuploid karyotype, but this was generally associated with senescence and was common to both PAH and controls. We also utilized ECFC to isolate the chromosomally abnormal cells from a mixed population of PAH PAEC. Analysis of PAEC harboring two different changes affecting chromosomes 1 and X demonstrated that both abnormalities were present in the same clone, indicating they originated in a common ancestral cell. In a second case, with a partial duplication of chromosome 17, clones carrying the duplication were more frequent at later passages than chromosomally normal clones from the same PAEC culture, suggesting the rearrangement may confer a proliferative advantage. Overall, this small study suggests that endothelial cells from PAH lungs are stable in culture, but that when chromosome abnormalities do occur, they may confer a selective advantage that allows expansion of the abnormal cell population and could contribute to lung vascular remodeling in vivo.

The integration of stem cell technology and cell sheet engineering improved the potential use of cell sheet products in regenerative medicine. This review will discuss the use of mesenchymal stem cells (MSCs) in cell sheet-based tissue engineering. Besides their adhesiveness to plastic surfaces and their extensive differentiation potential in vitro, MSCs are easily accessible, expandable in vitro with acceptable genomic stability, and few ethical issues. With all these advantages, they are extremely well suited for cell sheet-based tissue engineering. This review will focus on the use of MSC sheets in osteogenic tissue engineering. Potential application techniques with or without scaffolds and/or grafts will be discussed. Finally, the importance of osteogenic induction of these MSC sheets in orthopaedic applications will be demonstrated.

Background: Genomically instable (GI) chronic lymphocytic leukemia (CLL) is characterized by frequent alterations in DNA-damage response (DDR) genes (e.g. TP53, ATM) and related pathways. Conversely, pathogenic networks in CLL cases which maintain genomic integrity and operate with a functional DDR remain incompletely described. Methods: Molecular profiling was conducted on CD19 sorted samples derived from patients registered on the CLL8 study (1st-line, FC vs. FCR) for gene expression (GEP)(n=337, Exon 1.0 ST arrays, Affymetrix), copy number aberrations (CNAs) (n=309, SNP Arrays 6.0, Affymetrix) and mutation analyses/signature projections (n=171, whole exome sequencing, Illumina). FISH, IGHV and TP53 mutation analysis was conducted at trial enrolment. Results: Unsupervised consensus clustering (k=2-6) on variably expressed genes (SD>0.5) was used for class discovery. Two small, but highly differentiated clusters were identified, characterized through NRIP1 and EBF1/tri12. GSEA also segregated the remaining samples into four major clusters showing signatures of inflammation (I) and without inflammation (NI). These clusters were further segregated into GI-CLL clusters with increased “DNA-repair” or clusters with “epithelial-mesenchymal transition”-like signatures (EMT-L). Variability for del(17p)/TP53 mutation was found across clusters (p

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic alterations in glioblastomas (GBMs), occurring in about half of all patients. Here, we demonstrated that MTAP loss compromises the proteostasis of genomic stability guardian, H2AX, via disrupting a signaling cascade of PRMT5-RNF168-SMURF2. We showed that PRMT5 sustains the expression of RNF168, an E3 ubiquitin ligase essential for cellular response to DNA damage. Suppression of PRMT5 function, as occurring in MTAP-null GBM cells, attenuates the expression of RNF168, which consequently leads to degradation of H2AX protein by a HECT-type E3 ubiquitin ligase, SMURF2. We revealed that RNF168 and SMURF2, serving as a stabilizer and destabilizer of H2AX respectively, functionally oppose each other via their dynamic interactions with H2AX. In supporting the important role of this PRMT5-RNF168-SMURF2 signaling cascade in controlling H2AX homeostasis, MTAP-null GBM cells display a compromised DNA damage response, highlighted by higher levels of DNA damage spontaneously or in response to genotoxic agents. Collectively, these results identify a novel signaling cascade that is essential to the DNA damage response, reveal the profound impact of MTAP loss on GBM cells, and suggest novel therapeutic opportunities.

Efficient DNA repair is critical for cell survival following exposure to DNA topoisomerase I (Top1) inhibitors camptothecin, a nature product from which the common chemotherapeutic drugs irinotecan and topotecan are derived. The camptothecin-derived agents exert their antitumor activities by specifically stabilizing the Top1–DNA covalent complexes (Top1cc) and blocking the DNA religation step. When exposed to these DNA damage agents, tumor cells quickly activate DNA damage response. This allows sufficient time to remove the Top1ccs and prevent tumor cells from apoptosis. Several repair pathways have been implicated in this process. One of the most relevant repair modes is DNA single strand break repair (SSBR) pathway. The expression level or mutagenesis of specific repair factors involved in SSBR pathway may play an indispensable role in individual’s capacity of repairing camptothecin induced DNA damage. Therefore, understanding of the tolerance pathways counteracted to camptothecin cytotoxicity is crucial in alleviating chemotherapy resistance. This review focus on the SSBR pathway in repair camptothecin induced DNA damage, aiming to provide insights into the potential molecular determinants of camptothecin chemosensitivity.

The development of multicellular organisms and the maintenance of its tissues relies on mitosis. However, this process represents a major challenge for genomic stability as each time a cell division occurs there are multiple steps where errors can lead to an abnormal chromosomal content in daughter cells - aneuploidy. Aneuploidy was first postulated to act as a tumour promoting agent over one century ago. Since then, we have learned to appreciate the complexity involving the cellular responses to aneuploidy and to value the importance of models where aneuploidy is induced in vivo and in a cell-type specific manner. Recent data suggests that stem cells evolved a distinct response to aneuploidy, being able to survive and proliferate as aneuploid. Since stem cells are the main cells responsible for tissue renewal, it is of the utmost importance to place the spotlight on stem cells within the aneuploidy field. Here, we briefly review some of the biological mechanisms implicated in aneuploidy, the relationship between aneuploidy and tissue pathologies, and summarize the most recent findings in Drosophila on how tissue stem cells respond to aneuploidy. Once we understand how stem cell behavior is impacted by aneuploidy, we might be able to better describe the complicated link between aneuploidy and tumourigenesis.

Telomeres are complex and dynamic structures whose functions and composition change during the cell cycle and development. Telomeric transcripts are essential components of telomeres. Transcription regulation and cellular levels of telomeric RNAs are closely associated with the control of telomere length, formation of telomeric chromatin, telomere replication, and regulation of non-telomeric gene transcription, which indicates a critical regulatory role of telomeric RNAs in telomere protection and transmission of signals about the state of telomeres to cellular genes. The studies of telomeric transcriptome in early Drosophila development have revealed a new level of genomic stability regulation involving telomer-ic RNAs. Due to their ability to interact with multiple proteins and to translocate in the cell, telomeric transcripts are impor-tant participants of telomeric signaling pathways, whose mechanisms are still to be understood at the organism level.

NORAD is a highly-conserved and abundant long noncoding RNA (lncRNA) that is required for maintenance of genomic stability in mammals. Although initial characterization of NORAD established it as a negative regulator of PUMILIO (PUM) proteins in the cytoplasm, a nuclear role for NORAD in genome maintenance through an interaction with the RNA binding protein RBMX has also been reported. Here we addressed the relative contributions of NORAD:PUM and NORAD:RBMX interactions to the regulation of genomic stability by this lncRNA. Extensive RNA FISH and fractionation experiments established that NORAD localizes predominantly to the cytoplasm with or without DNA damage. Moreover, genetic rescue experiments demonstrated that PUM binding is required for maintenance of genomic stability by NORAD whereas binding of RBMX is dispensable for this function. These data therefore establish an essential role for the NORAD:PUM interaction in genome maintenance and provide a foundation for further mechanistic dissection of this pathway.