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Histone modifications are catalyzed and recognized by specific proteins to regulate dynamic DNA metabolism processes. NSD2 is a histone H3 lysine 36 (H3K36)‐specific methyltransferase that is associated with both various transcription regulators and DNA repair factors. Specifically, it has been implicated in the repair of DNA double‐strand breaks (DSBs); however, the role of NSD2 during DSB repair remains enigmatic. Here, we show that NSD2 does not accumulate at DSB sites and that it is not further mobilized by DSB formation. Using three different DSB repair reporter systems, which contained the endonuclease site in the active thymidine kinase gene (TK) locus, we demonstrated separate dose‐dependent effects of NSD2 on homologous recombination (HR), canonical‐non‐homologous end joining (c‐NHEJ), and non‐canonical‐NHEJ (non‐c‐NHEJ). Endogenous NSD2 has a role in repressing non‐c‐NHEJ, without affecting DSB repair efficiency by HR or total NHEJ. Furthermore, overexpression of NSD2 promotes c‐NHEJ repair and suppresses HR repair. Therefore, we propose that NSD2 has functions in chromatin integrity at the active regions during DSB repair. [ABSTRACT FROM AUTHOR]

A robust and efficient cellular response to lysosomal membrane damage prevents leakage from the lysosome lumen into the cytoplasm. This response is understood to happen through either lysosomal membrane repair or lysophagy. Here we report exocytosis as a third response mechanism to lysosomal damage, which is further potentiated when membrane repair or lysosomal degradation mechanisms are impaired. We show that Connexin43 (Cx43), a protein canonically associated with gap junctions, is recruited from the plasma membrane to damaged lysosomes, promoting their secretion and accelerating cell recovery. The effects of Cx43 on lysosome exocytosis are mediated by a reorganization of the actin cytoskeleton that increases plasma membrane fluidity and decreases cell stiffness. Furthermore, we demonstrate that Cx43 interacts with the actin nucleator Arp2, the activity of which was shown to be necessary for Cx43-mediated actin rearrangement and lysosomal exocytosis following damage. These results define a novel mechanism of lysosomal quality control whereby Cx43-mediated actin remodelling potentiates the secretion of damaged lysosomes. Synopsis: Damaged lysosomes are marked for either membrane repair or removal by lysophagy. This report describes a third pathway, Connexin43-mediated lysosome exocytosis, that is also able to restore cell homeostasis. Lysosomal exocytosis upon injury is enhanced by inhibiting either lysophagy or lysosomal membrane repair. Connexin43 (Cx43) at the plasma membrane is recruited to Galectin3-positive damaged lysosomes via AP2-dependent endocytosis. Exocytosis of damaged lysosomes is potentiated by Cx43 through an Arp2-mediated remodelling of the actin cytoskeleton. Cx43-mediated lysosome exocytosis is relevant in pathological conditions such as Salmonella infection or the lysosomal storage disorder Niemann-Pick disease. Damaged lysosomes can be expelled from the cell in a Connexin43-dependent manner. [ABSTRACT FROM AUTHOR]

Topoisomerase 1 (Top1) controls DNA topology, relieves DNA supercoiling during replication and transcription, and is critical for mitotic progression to the G1 phase. Tyrosyl-DNA phosphodiesterase 1 (TDP1) mediates the removal of trapped Top1-DNA covalent complexes (Top1cc). Here, we identify CDK1-dependent phosphorylation of TDP1 at residue S61 during mitosis. A TDP1 variant defective for S61 phosphorylation (TDP1-S61A) is trapped on the mitotic chromosomes, triggering DNA damage and mitotic defects. Moreover, we show that Top1cc repair in mitosis occurs via a MUS81-dependent DNA repair mechanism. Replication stress induced by camptothecin or aphidicolin leads to TDP1-S61A enrichment at common fragile sites, which over-stimulates MUS81-dependent chromatid breaks, anaphase bridges, and micronuclei, ultimately culminating in the formation of 53BP1 nuclear bodies during G1 phase. Our findings provide new insights into the cell cycle-dependent regulation of TDP1 dynamics for the repair of trapped Top1-DNA covalent complexes during mitosis that prevents genomic instability following replication stress. Synopsis: Tyrosyl-DNA phosphodiesterase 1 (TDP1) supports repair of trapped Top1-DNA covalent complexes. This study shows that TDP1 is phosphorylated at its residue S61 by CDK1 during mitosis, countering DNA damage, mitotic abnormalities, and chromosomal instability upon replication stress. CDK1 phosphorylates TDP1 at S61 during mitosis. TDP1 defective for S61 phosphorylation (TDP1-S61A) is retained on the mitotic chromosomes, triggering DNA damage and mitotic defects. A MUS81-dependent pathway is predominantly responsible for mitotic clearing of trapped Top1-DNA covalent complexes. MUS81 depletion rescues chromosomal abnormalities in TDP1-S61A-expressing cells. Blocking CDK1-mediated TDP1 phosphorylation results in increased levels of DNA damage and genomic instability upon replication stress. [ABSTRACT FROM AUTHOR]

ABSTRACT Genotoxic stress activates the DNA‐damage response (DDR) signalling cascades responsible for maintaining genome integrity. Downstream DNA repair pathways include the tyrosyl‐DNA phosphodiesterase 1 (TDP1) enzyme that hydrolyses the phosphodiester bond between the tyrosine of topoisomerase I (TopI) and 3′‐phosphate of DNA. The plant TDP1 subfamily contains the canonical TDP1α gene and the TDP1β gene whose functions are not fully elucidated. The current study proposes to investigate the involvement of TDP1 genes in DDR‐related processes by using Arabidopsis thaliana mutants treated with genotoxic agents. The phenotypic and molecular characterization of tdp1α, tdp1β and tdp1α/β mutants treated with cisplatin (CIS), curcumin (CUR), NSC120686 (NSC), zeocin (ZEO), and camptothecin (CPT), evidenced that while tdp1β was highly sensitive to CIS and CPT, tdp1α was more sensitive to NSC. Gene expression analyses showing upregulation of the TDP2 gene in the double mutant indicate the presence of compensatory mechanisms. The downregulation of POL2A gene in the tdp1β mutant along with the upregulation of the TDP1β gene in pol2a mutants, together with its sensitivity to replication inhibitors (CIS, CTP), point towards a function of this gene in the response to replication stress. Therefore, this study brings novel information relative to the activity of TDP1 genes in plants. [ABSTRACT FROM AUTHOR]

The document provides information about the journal "Environmental & Molecular Mutagenesis," including its officers, councilors, editors, and administration. The journal covers a wide range of topics related to environmental mutagenesis, such as DNA damage, genetics, and public health. It aims to publish original research, reviews, and commentaries that are relevant to researchers, regulatory decision-makers, and public health policy. The document also includes guidelines for authors submitting manuscripts, including formatting, authorship credit, conflict of interest declarations, and publication ethics. Additionally, it provides information about the 55th Annual Meeting of the Environmental Mutagenesis and Genomics Society, including sponsors and abstracts. [Extracted from the article]

This document is a collection of abstracts from the 55th Annual Meeting of the Environmental Mutagenesis and Genomics Society. The abstracts cover a wide range of topics related to DNA discoveries, DNA repair systems, the human pangenome project, epigenetic inheritance, maintaining genome stability, and applying new methods for epigenetics research. The abstracts provide valuable insights into the latest research and advancements in these areas, making it a valuable resource for researchers and those interested in these topics. The given text is a list of names and affiliations of various individuals involved in research and studies related to different topics. The list includes researchers from diverse backgrounds and fields of study, such as biology, chemistry, medicine, and environmental science. These individuals have contributed to various research projects and publications, and their expertise covers a wide range of subjects. The list can be a valuable resource for library patrons conducting research on specific topics and looking for experts in their respective fields. [Extracted from the article]

Background: Homologous recombination deficiency (HRD) is a biomarker that predicts response to ovarian cancer treatment with poly (ADP‐ribose) polymerase (PARP) inhibitors or breast cancer treatment with first‐line platinum‐based chemotherapy. However, there are few studies on the prognosis of lung cancer patients treated with immune checkpoint inhibitor (ICI) therapy using HRD as a biomarker. Methods: We studied the relationship between HRD status and the effectiveness of first‐line ICI‐based therapy in EGFR/ALK wild‐type metastatic non‐small cell lung cancer patients (NSCLC) patients. Results: This study included 22 treatment naïve NSCLC patients. The HRD score ranged from −26.37 to 92.34, with an average of 24.57. Based on analysis of the progression‐free survival (PFS) data from the included NSCLC patients, threshold traversal was carried out. HRD (+) was defined as an HRD score of 31 or higher. Kaplan–Meier PFS survival analysis showed prolonged median PFS (mPFS) in NSCLC patients with HRD (+) versus HRD (−) (N/A vs. 7.0 ms, log‐rank p = 0.029; HR 0.20, 95% CI: 0.04–0.96, likelihood‐ratio p = 0.03). In patients with PD‐L1 TPS ≥50% and HRD score ≥31 (co‐status high), the mPFS was temporarily not reached during the follow‐up period. In patients with PD‐L1 TPS <1% and HRD score <31, the mPFS was 3 ms. Cox regression analysis showed that the hazard ratio of the co‐status was 0.14 (95% CI: 0.04–0.54), which was a good prognostic factor, and the prognostic effect of co‐status was better than that of HRD score alone. Conclusion: The HRD status can be identified as an independent significance in NSCLC patients treated with first‐line ICI‐based therapy. [ABSTRACT FROM AUTHOR]

Genotoxic stress, arising from various environmental sources and endogenous cellular processes, pose a constant threat to genomic stability. Cells have evolved intricate mechanisms to detect and repair DNA damage, orchestrating a robust genotoxic stress response to safeguard the integrity of the genome. Recent research has shed light on the crucial role of co‐ and post‐transcriptional regulatory mechanisms in modulating the cellular response to genotoxic stress. Here we highlight recent advances illustrating the intricate interplay between pre‐mRNA processing, with a focus on 3′‐end processing, and genotoxic stress response. [ABSTRACT FROM AUTHOR]

Premature ovarian insufficiency is a common form of female infertility affecting up to 4% of women and characterised by amenorrhea with elevated gonadotropin before the age of 40. Oocytes require controlled DNA breakage and repair for homologous recombination and the maintenance of oocyte integrity. Biallelic disruption of the DNA damage repair gene, Fanconi anemia complementation group A (FANCA), is a common cause of Fanconi anaemia, a syndrome characterised by bone marrow failure, cancer predisposition, physical anomalies and POI. There is ongoing dispute about the role of heterozygous FANCA variants in POI pathogenesis, with insufficient evidence supporting causation. Here, we have identified biallelic FANCA variants in French sisters presenting with POI, including a novel missense variant of uncertain significance and a likely pathogenic deletion that initially evaded detection. Functional studies indicated no discernible effect on DNA damage sensitivity in patient lymphoblasts. These novel FANCA variants add evidence that heterozygous loss of one allele is insufficient to cause DNA damage sensitivity and POI. We propose that intragenic deletions, that are relatively common in FANCA, may be missed without careful analysis, and could explain the presumed causation of heterozygous variants. Accurate variant curation is critical to optimise patient care and outcomes. [ABSTRACT FROM AUTHOR]

ABSTRACT Transformation, the uptake of DNA directly from the environment, is a major driver of gene flow in microbial populations. In bacteria, DNA uptake requires a nuclease that processes dsDNA to ssDNA, which is subsequently transferred into the cell and incorporated into the genome. However, the process of DNA uptake in archaea is still unknown. Previously, we cataloged genes essential to natural transformation in Methanococcus maripaludis, but few homologs of bacterial transformation‐associated genes were identified. Here, we characterize one gene, MMJJ_16440 (named here as ecnA), to be an extracellular nuclease. We show that EcnA is Ca2+‐activated, present on the cell surface, and essential for transformation. While EcnA can degrade several forms of DNA, the highest activity was observed with ssDNA as a substrate. Activity was also observed with circular dsDNA, suggesting that EcnA is an endonuclease. This is the first biochemical characterization of a transformation‐associated protein in a member of the archaeal domain and suggests that both archaeal and bacterial transformation initiate in an analogous fashion. [ABSTRACT FROM AUTHOR]

BACKGROUND: Leucine (Leu) is an essential amino acid that facilitates skeletal muscle satellite cell differentiation, yet its mechanism remains underexplored. Sestrin2 (SESN2) serves as a Leu sensor, binding directly to Leu, while ribophorin II (RPN2) acts as a signaling factor in multiple pathways. This study aimed to elucidate Leu's impact on mouse C2C12 cell differentiation and skeletal muscle injury repair by modulating RPN2 expression through SESN2, offering a theoretical foundation for clinical skeletal muscle injury prevention and treatment. RESULTS: Leu addition promoted C2C12 cell differentiation compared to the control, enhancing early differentiation via myogenic determinant (MYOD) up‐regulation. Sequencing revealed SESN2 binding to and interacting with RPN2. RPN2 overexpression up‐regulated MYOD, myogenin and myosin heavy chain 2, concurrently decreased p‐GSK3β and increased nuclear β‐catenin. Conversely, RPN2 knockdown yielded opposite results. Combining RPN2 knockdown with Leu rescued increased p‐GSK3β and decreased nuclear β‐catenin compared to Leu absence. Hematoxylin and eosin staining results showed that Leu addition accelerated mouse muscle damage repair, up‐regulating Pax7, MYOD and RPN2 in the cytoplasm, and nuclear β‐catenin, confirming that the role of Leu in muscle injury repair was consistent with the results for C2C12 cells. CONCLUSION: Leu, bound with SESN2, up‐regulated RPN2 expression, activated the GSK3β/β‐catenin pathway, enhanced C2C12 differentiation and expedited skeletal muscle damage repair. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

With the rise of bacterial infections and antibiotic resistance, spectroscopic devices originally developed for bacterial detection have shown promise to rapidly identify bacterial strains and determine the ratio of live to dead bacteria. However, the detection of the photoreactivated pathogens remains a critical concern. This study utilizes fluorescence and Raman spectroscopy to analyze bacterial responses to UV irradiation and subsequent photoreactivation. Our experimental results reveal limitations in fluorescence spectroscopy for detecting photoreactivated bacteria, as the intense fluorescence of tryptophan and tyrosine amino acids masks the fluorescence emitted by thymine molecules. Conversely, Raman spectroscopy proves more effective, showing a detectable decrease in band intensities of E. coli bacteria at 1248 and 1665 cm−1 after exposure to UVC radiation. Subsequent UVA irradiation results in the partial restoration of these band intensities, indicating DNA repair and bacterial photoreactivation. This enhanced understanding aims to improve the accuracy and effectiveness of these spectroscopic tools in clinical and environmental settings. [ABSTRACT FROM AUTHOR]

Ferroptosis is a form of regulated cell death that can be modulated by small molecules and has the potential for the development of therapeutics for oncology. Although excessive lipid peroxidation is the defining hallmark of ferroptosis, DNA damage may also play a significant role. In this study, a potential mechanistic role for MIF in homologous recombination (HR) DNA repair is identified. The inhibition or genetic depletion of MIF or other HR proteins, such as breast cancer type 1 susceptibility protein (BRCA1), is demonstrated to significantly enhance the sensitivity of cells to ferroptosis. The interference with HR results in the translocation of the tumor suppressor protein p53 to the mitochondria, which in turn stimulates the production of reactive oxygen species. Taken together, the findings demonstrate that MIF‐directed small molecules enhance ferroptosis via a putative MIF‐BRCA1‐RAD51 axis in HR, which causes resistance to ferroptosis. This suggests a potential novel druggable route to enhance ferroptosis by targeted anticancer therapeutics in the future. [ABSTRACT FROM AUTHOR]

Cells have evolved a robust and highly regulated DNA damage response to preserve their genomic integrity. Although increasing evidence highlights the relevance of RNA regulation, our understanding of its impact on a fully efficient DNA damage response remains limited. Here, through a targeted CRISPR-knockout screen, we identify RNA-binding proteins and modifiers that participate in the p53 response. Among the top hits, we find the m6A reader YTHDC1 as a master regulator of p53 expression. YTHDC1 binds to the transcription start sites of TP53 and other genes involved in the DNA damage response, promoting their transcriptional elongation. YTHDC1 deficiency also causes the retention of introns and therefore aberrant protein production of key DNA damage factors. While YTHDC1-mediated intron retention requires m6A, TP53 transcriptional pause-release is promoted by YTHDC1 independently of m6A. Depletion of YTHDC1 causes genomic instability and aberrant cancer cell proliferation mediated by genes regulated by YTHDC1. Our results uncover YTHDC1 as an orchestrator of the DNA damage response through distinct mechanisms of co-transcriptional mRNA regulation. Synopsis: The DNA damage response (DDR) is critical to preserve genomic integrity, and p53 plays a central role in this process. Here, we show that YTHDC1 controls the correct expression of TP53 mRNA as well as splicing of key DDR factors in a m6A-independent and -dependent manner, respectively. CRISPR knockout screening focused on RNA regulators identifies YTHDC1 as required for p53-dependent reporter gene activation. YTHDC1 directly controls TP53 expression through promoter-proximal RNAPII pause-release in a m6A-independent mechanism. In addition, YTHDC1 directly regulates the efficient splicing of ATR, BIRC6 and SETX transcripts in a m6A-dependent manner. Depletion of YTHDC1 results in accumulated DNA damage, reduced proliferation and tumorigenicity of lung cancer cells, caused by deregulation of DDR factors. m6A reader YTHDC1 contributes to genome integrity by promoting p53 expression and controling pre-mRNA splicing of key DNA damage response regulators. [ABSTRACT FROM AUTHOR]

Cellular senescence is a response to many stressful insults. DNA damage is a consistent feature of senescent cells, but in many cases its source remains unknown. Here, we identify the cellular endonuclease caspase-activated DNase (CAD) as a critical factor in the initiation of senescence. During apoptosis, CAD is activated by caspases and cleaves the genomic DNA of the dying cell. The CAD DNase is also activated by sub-lethal signals in the apoptotic pathway, causing DNA damage in the absence of cell death. We show that sub-lethal signals in the mitochondrial apoptotic pathway induce CAD-dependent senescence. Inducers of cellular senescence, such as oncogenic RAS, type-I interferon, and doxorubicin treatment, also depend on CAD presence for senescence induction. By directly activating CAD experimentally, we demonstrate that its activity is sufficient to induce senescence in human cells. We further investigate the contribution of CAD to senescence in vivo and find substantially reduced signs of senescence in organs of ageing CAD-deficient mice. Our results show that CAD-induced DNA damage in response to various stimuli is an essential contributor to cellular senescence. Synopsis: Senescent cells are characterized by DNA damage, but the underlying mechanisms in many contexts remain little understood. Our study identifies and characterizes an important contribution of the caspase-activated DNase (CAD) to senescence-associated DNA damage in vitro and in mice. CAD is required for a normal cellular senescence response to various stimuli. CAD activation is sufficient for the induction of senescence in vitro. CAD-dependent activation of cGAS induces production of components of the senescence-associated secretory phenotype. While strong apoptotic stimuli kill the cell, weaker stimuli can cause caspase activation at sub-lethal levels, leading to CAD activation and senescence. Sub-lethal apoptotic signals activate the caspase-activated DNase (CAD), leading to genomic DNA cleavage and the induction of senescence. [ABSTRACT FROM AUTHOR]

Background: Monoallelic germline pathogenic variants (GPVs) in five Fanconi anemia (FA) genes (BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO) confer an increased risk of breast (BC) and/or ovarian (OC) cancer, but the role of GPVs in 17 other FA genes remains unclear. Methods: Here, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk. Results: The frequency of truncating GPVs in FANCG did not differ between BC (20/10,204; 0.20%) and OC (8/2966; 0.27%) patients compared to controls (6/3250; 0.18%). In addition, only one out of five tumor samples showed loss‐of‐heterozygosity of the wild‐type FANCG allele. Finally, none of the nine functionally tested rare recurrent missense FANCG variants impaired DNA repair activities (FANCD2 monoubiquitination and FANCD2 foci formation) upon DNA damage, in contrast to all tested FANCG truncations. Conclusion: Our study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC. [ABSTRACT FROM AUTHOR]

Background Results Physical, chemical, and biological factors in the environment constantly influence in vivo and in vitro biological processes, including diverse histone modifications involved in cancer and metabolism. However, the intricate mechanisms of acetylation regulation remain poorly elucidated. In mammalian spermatogenesis, acetylation plays a crucial role in repairing double‐strand DNA breaks, regulating gene transcription, and modulating various signaling pathways.This review summarizes the histone acetylation sites in the mouse testis and provides a comprehensive overview of how histone acetylation is involved in different stages of spermatogenesis under the regulation by histone deacetylases. The regulatory functions of various class histone deacetylases during spermatogenesis and the crossroad between histone acetylation and other histone modifications are highlighted. It is imperative to understand the mechanisms of histone acetylation regulated by histone deacetylases in spermatogenesis, which facilitates to prevent and treat infertility‐related diseases. [ABSTRACT FROM AUTHOR]

Background information Results Conclusions Significance Arpin, an Arp2/3 inhibitory protein, inhibits lamellipodial protrusions and cell migration. Arpin expression is lost in tumor cells of several cancer types.Here we analyzed expression levels of Arpin and various markers using Reverse Phase Protein Array (RPPA) in human mammary carcinomas. We found that Arpin protein levels were correlated with those of several DNA damage response markers. Arpin‐null cells display enhanced clustering of double stand breaks (DSBs) when cells are treated with a DNA damaging agent, in line with a previously described role of the Arp2/3 complex in promoting DSB clustering for homologous DNA repair (HDR) in the nucleus. Using a specific HDR assay, we further showed that Arpin depletion increased HDR efficiency two‐fold through its ability to inactivate the Arp2/3 complex.Arpin regulates both cell migration in the cytosol and HDR in the nucleus.Loss of Arpin expression coordinates enhanced cell migration with up‐regulated DNA repair, which is required when DNA damage is induced by active cell migration. [ABSTRACT FROM AUTHOR]

Objective Materials and Methods Results Conclusions Electronic cigarette (e‐cigarette) use among adults in the United States continues to rise. Particularly concerning is the impact of e‐cigarette aerosol inhalation on the oral mucosa. Aerosols are derived from a heated e‐liquid base of propylene glycol/glycerin (PG/G) often mixed with nicotine and chemical flavors. Of note, harmful and potentially harmful constituents (HPHCs), including metals and volatile organic compounds, have been detected in e‐cigarette aerosols. It remains unknown, however, whether aerosols exclusively derived from e‐liquid PG/G are detrimental to oral keratinocytes. The present study analyzed toxicological outcomes in normal oral keratinocytes exposed to model nicotine‐free, unflavored PG/G e‐liquid aerosols.Cell viability/cytotoxicity, genotoxicity, and immunoblotting assays were conducted in NOKSI, a gingiva‐derived oral keratinocyte cell line, following exposure to model e‐liquid aerosols or non‐aerosolized controls. The HPHC acrolein, reported to form DNA adducts in the buccal mucosa from e‐cigarette users, was also used in similar assays.PG/G e‐liquid aerosol extracts significantly enhanced cytotoxic and DNA damaging responses in NOKSI cells when compared to non‐aerosolized e‐liquid treatment. Acrolein treatment led to similar results.The aerosolization process of PG/G e‐liquid is a critical determinant of marked cytotoxic and genotoxic stimuli in oral keratinocytes. [ABSTRACT FROM AUTHOR]

The key DNA repair enzyme DNA-PKcs has several and important cellular functions. Loss of DNA-PKcs activity in mice has revealed essential roles in immune and nervous systems. In humans, DNA-PKcs is a critical factor for brain development and function since mutation of the prkdc gene causes severe neurological deficits such as microcephaly and seizures, predicting yet unknown roles of DNA-PKcs in neurons. Here we show that DNA-PKcs modulates synaptic plasticity. We demonstrate that DNA-PKcs localizes at synapses and phosphorylates PSD-95 at newly identified residues controlling PSD-95 protein stability. DNA-PKcs −/− mice are characterized by impaired Long-Term Potentiation (LTP), changes in neuronal morphology, and reduced levels of postsynaptic proteins. A PSD-95 mutant that is constitutively phosphorylated rescues LTP impairment when over-expressed in DNA-PKcs −/− mice. Our study identifies an emergent physiological function of DNA-PKcs in regulating neuronal plasticity, beyond genome stability. Synopsis: DNA-PKcs has a role in neuronal plasticity via PSD-95 phosphorylation and regulation of its protein stability, revealing a physiological role beyond its function in DNA repair. Synaptic DNA-PKcs phosphorylates PSD-95 at newly identified residues. DNA-PKcs phopshorylation controls PSD-95 protein stability. Lack of DNA-PKcs affects synaptic plasticity. Constitutively phosphorylated PSD-95 rescues LTP impairment when over-expressed in DNA-PKcs −/− mice. DNA-PKcs has a role in neuronal plasticity via PSD-95 phosphorylation and regulation of its protein stability, revealing a physiological role beyond its function in DNA repair. [ABSTRACT FROM AUTHOR]

Breast tumor‐initiating cells (BTICs) of triple‐negative breast cancer (TNBC) tissues actively repair DNA and are resistant to treatments including chemotherapy, radiotherapy, and targeted therapy. Herein, it is found that a previously reported secreted protein, sclerostin domain containing 1 (SOSTDC1), is abundantly expressed in BTICs of TNBC cells and positively correlated with a poor patient prognosis. SOSTDC1 knockdown impairs homologous recombination (HR) repair, BTIC maintenance, and sensitized bulk cells and BTICs to Olaparib. Mechanistically, following Olaparib treatment, SOSTDC1 translocates to the nucleus in an importin‐α dependent manner. Nuclear SOSTDC1 interacts with the N‐terminus of the nucleoprotein, chromatin helicase DNA‐binding factor (CHD1), to promote HR repair and BTIC maintenance. Furthermore, nuclear SOSTDC1 bound to β‐transducin repeat‐containing protein (β‐TrCP) binding motifs of CHD1 is found, thereby blocking the β‐TrCP‐CHD1 interaction and inhibiting β‐TrCP‐mediated CHD1 ubiquitination and degradation. Collectively, these findings identify a novel nuclear SOSTDC1 pathway in regulating HR repair and BTIC maintenance, providing insight into the TNBC therapeutic strategies. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the most lethal gynecological malignancy and is often associated with both DNA repair deficiency and extensive metabolic reprogramming. While still emerging, the interplay between these pathways can affect ovarian cancer phenotypes, including therapeutic resistance to the DNA damaging agents that are standard‐of‐care for this tumor type. In this review, we will discuss what is currently known about cellular metabolic rewiring in ovarian cancer that may impact DNA damage and repair in addition to highlighting how specific DNA repair proteins also promote metabolic changes. We will also discuss relevant data from other cancers that could be used to inform ovarian cancer therapeutic strategies. Changes in the choice of DNA repair mechanism adopted by ovarian cancer are a major factor in promoting therapeutic resistance. Therefore, the impact of metabolic reprogramming on DNA repair mechanisms in ovarian cancer has major clinical implications for targeted combination therapies for the treatment of this devastating disease. [ABSTRACT FROM AUTHOR]

The Three Prime Repair Exonuclease 1 (TREX1) has been implicated in several pathologies characterized by chronic and inborn inflammation. Aberrant innate immunity caused by DNA sensing through the cGAS‐STING pathway has been proposed to play a major role in the etiology of these interferonopathies. However, the molecular source of this DNA sensing and the possible involvement of TREX1 in genome (in)stability remains poorly understood. Recent findings reignite the debate about the cellular functions performed by TREX1 nuclease, notably in chromosome biology and stability. Here I put into perspective recent findings that suggest that TREX1 is at the crossroads of DNA damage response and inflammation in different pathological contexts. [ABSTRACT FROM AUTHOR]

Summary: Throughout their lifecycle, plants are subjected to DNA damage from various sources, both environmental and endogenous. Investigating the mechanisms of the DNA damage response (DDR) is essential to unravel how plants adapt to the changing environment, which can induce varying amounts of DNA damage.Using a combination of whole‐mount single‐molecule RNA fluorescence in situ hybridization (WM‐smFISH) and plant cell cycle reporter lines, we investigated the transcriptional activation of a key homologous recombination (HR) gene, RAD51, in response to increasing amounts of DNA damage in Arabidopsis thaliana roots.The results uncover consistent variations in RAD51 transcriptional response and cell cycle arrest among distinct cell types and developmental zones. Furthermore, we demonstrate that DNA damage induced by genotoxic stress results in RAD51 transcription throughout the whole cell cycle, dissociating its traditional link with S/G2 phases.This work advances the current comprehension of DNA damage response in plants by demonstrating quantitative differences in DDR activation. In addition, it reveals new associations with the cell cycle and cell types, providing crucial insights for further studies of the broader response mechanisms in plants. [ABSTRACT FROM AUTHOR]

Interhomolog recombination in meiosis is mediated by the Dmc1 recombinase. The Mei5‐Sae3 complex of Saccharomyces cerevisiae promotes Dmc1 assembly and functions with Dmc1 for homology‐mediated repair of meiotic DNA double‐strand breaks. How Mei5‐Sae3 facilitates Dmc1 assembly remains poorly understood. In this study, we created and characterized several mei5 mutants featuring the amino acid substitutions of basic residues. We found that Arg97 of Mei5, conserved in its ortholog, SFR1 (complex with SWI5), RAD51 mediator, in humans and other organisms, is critical for complex formation with Sae3 for Dmc1 assembly. Moreover, the substitution of either Arg117 or Lys133 with Ala in Mei5 resulted in the production of a C‐terminal truncated Mei5 protein during yeast meiosis. Notably, the shorter Mei5‐R117A protein was observed in meiotic cells but not in mitotic cells when expressed, suggesting a unique regulation of Dmc1‐mediated recombination by posttranslational processing of Mei5‐Sae3. [ABSTRACT FROM AUTHOR]

DNA double‐strand breaks (DSBs) are the most severe DNA lesions and need to be removed immediately to prevent loss of genomic information. Recently, it has been revealed that DSBs induce novel transcription from the cleavage sites in various species, resulting in RNAs being referred to as damage‐induced RNAs (diRNAs). While diRNA synthesis is an early event in the DNA damage response and plays an essential role in DSB repair activation, the location where diRNAs are newly generated in plants remains unclear, as does their transcriptional mechanism. Here, we performed the sequencing of polyadenylated (polyA) diRNAs that emerged around all DSB loci in Arabidopsis thaliana under the expression of the exogenous restriction enzyme Sbf I and observed 88 diRNAs transcribed via RNA polymerase II in 360 DSB loci. Most of the detected diRNAs originated within active genes and were transcribed from DSBs in a bidirectional manner. Furthermore, we found that diRNA elongation tends to terminate at the boundary of an endogenous gene located near DSB loci. Our results provide reliable evidence for understanding the importance of new transcription at DSBs and show that diRNA is a crucial factor for successful DSB repair. [ABSTRACT FROM AUTHOR]

NIMA‐related kinase 2 (NEK2) is a serine/threonine protein kinase that regulates mitosis and plays pivotal roles in cell cycle regulation and DNA damage repair. However, its function in porcine embryonic development is unknown. In this study, we used an NEK2‐specific inhibitor, JH295 (JH), to investigate the role of NEK2 in embryonic development and the underlying regulatory mechanisms. Inhibition of NEK2 after parthenogenesis activation or in vitro fertilization significantly reduced the rates of cleavage and blastocyst formation, the numbers of trophectoderm and total cells and the cellular survival rate compared with the control condition. NEK2 inhibition delayed cell cycle progression at all stages from interphase to cytokinesis during the first mitotic division; it caused abnormal nuclear morphology in two‐ and four‐cell stage embryos. Additionally, NEK2 inhibition significantly increased DNA damage and apoptosis, and it altered the expression levels of DNA damage repair‐ and apoptosis‐related genes. Intriguingly, NEK2 inhibition downregulated the expression of β‐catenin and its downstream target genes. To validate the relationship between Wnt/β‐catenin signalling and NEK2 during porcine embryonic development, we cultured porcine embryos in JH‐treated medium with or without CHIR99021, a Wnt activator. CHIR99021 co‐treatment strongly restored the developmental parameters reduced by NEK2 inhibition to control levels. Our findings suggest that NEK2 plays an essential role in porcine embryonic development by regulating DNA damage repair and normal mitotic division via the Wnt/β‐catenin signalling pathway. [ABSTRACT FROM AUTHOR]

Cyanobacteria have many biotechnological applications. Increasing their cultivation pH can assist in capturing carbon dioxide and avoiding invasion by other organisms. However, alkaline media may have adverse effects on cyanobacteria, such as reducing the Carbon‐Concentrating Mechanism's efficiency. Here, we cultivated two halo‐alkaliphilic cyanobacteria consortia in chemostats at pH 10.2–11.4. One consortium was dominated by Ca. Sodalinema alkaliphilum, the other by a species of Nodosilinea. These two cyanobacteria dominate natural communities in Canadian and Asian alkaline soda lakes. We show that increasing the pH decreased biomass yield. This decrease was caused, in part, by a dramatic increase in carbon transfer to heterotrophs. At pH 11.4, cyanobacterial growth became limited by bicarbonate uptake, which was mainly ATP dependent. In parallel, the higher the pH, the more sensitive cyanobacteria became to light, resulting in photoinhibition and upregulation of DNA repair systems. [ABSTRACT FROM AUTHOR]

SUMMARY: DNA–protein crosslinks (DPCs) are highly toxic DNA lesions represented by proteins covalently bound to the DNA. Persisting DPCs interfere with fundamental genetic processes such as DNA replication and transcription. Cytidine analog zebularine (ZEB) has been shown to crosslink DNA METHYLTRANSFERASE1 (MET1). Recently, we uncovered a critical role of the SMC5/6‐mediated SUMOylation in the repair of DPCs. In an ongoing genetic screen, we identified two additional candidates, HYPERSENSITIVE TO ZEBULARINE 2 and 3, that were mapped to REGULATOR OF TELOMERE ELONGATION 1 (RTEL1) and polymerase TEBICHI (TEB), respectively. By monitoring the growth of hze2 and hze3 plants in response to zebularine, we show the importance of homologous recombination (HR) factor RTEL1 and microhomology‐mediated end‐joining (MMEJ) polymerase TEB in the repair of MET1‐DPCs. Moreover, genetic interaction and sensitivity assays showed the interdependency of SMC5/6 complex, HR, and MMEJ in the homology‐directed repair of MET1‐DPCs in Arabidopsis. Altogether, we provide evidence that MET1‐DPC repair in plants is more complex than originally expected. Significance Statement: DNA–protein crosslinks (DPCs) are highly toxic DNA lesions represented by proteins covalently bound to the DNA. We show the importance of homologous recombination factor RTEL1 and microhomology‐mediated end joining polymerase TEB and their interdependency with the SMC5/6 complex in the repair of DNA METHYLTRANSFERASE1‐DPCs. This suggests a complex network of pathways detoxifying DPCs in plants. [ABSTRACT FROM AUTHOR]

SUMMARY: Structural maintenance of chromosome (SMC) complexes play roles in cohesion, condensation, replication, transcription, and DNA repair. Their cores are composed of SMC proteins with a unique structure consisting of an ATPase head, long arm, and hinge. SMC complexes form long rod‐like structures, which can change to ring‐like and elbow‐bent conformations upon binding ATP, DNA, and other regulatory factors. These SMC dynamic conformational changes are involved in their loading, translocation, and DNA loop extrusion. Here, we examined the binding and role of the PpNSE5 regulatory factor of Physcomitrium patens PpSMC5/6 complex. We found that the PpNSE5 C‐terminal half (aa230–505) is required for binding to its PpNSE6 partner, while the N‐terminal half (aa1–230) binds PpSMC subunits. Specifically, the first 71 amino acids of PpNSE5 were required for binding to PpSMC6. Interestingly, the PpNSE5 binding required the PpSMC6 head‐proximal joint region and PpSMC5 hinge‐proximal arm, suggesting a long distance between binding sites on PpSMC5 and PpSMC6 arms. Therefore, we hypothesize that PpNSE5 either links two antiparallel SMC5/6 complexes or binds one SMC5/6 in elbow‐bent conformation, the later model being consistent with the role of NSE5/NSE6 dimer as SMC5/6 loading factor to DNA lesions. In addition, we generated the P. patens Ppnse5KO1 mutant line with an N‐terminally truncated version of PpNSE5, which exhibited DNA repair defects while keeping a normal number of rDNA repeats. As the first 71 amino acids of PpNSE5 are required for PpSMC6 binding, our results suggest the role of PpNSE5–PpSMC6 interaction in SMC5/6 loading to DNA lesions. [ABSTRACT FROM AUTHOR]

Aims: Mutations in the MAPT gene encoding tau protein can cause autosomal dominant neurodegenerative tauopathies including frontotemporal dementia (often with Parkinsonism). In Alzheimer's disease, the most common tauopathy, synapse loss is the strongest pathological correlate of cognitive decline. Recently, Positron Emission Tomography (PET) imaging with synaptic tracers revealed clinically relevant loss of synapses in primary tauopathies; however, the molecular mechanisms leading to synapse degeneration in primary tauopathies remain largely unknown. In this study, we examined post‐mortem brain tissue from people who died with frontotemporal dementia with tau pathology (FTDtau) caused by the MAPT intronic exon 10 + 16 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule‐binding domains. Methods: We used RNA sequencing and histopathology to examine temporal cortex and visual cortex, to look for molecular phenotypes compared to age, sex and RNA integrity matched participants who died without neurological disease (n = 12 FTDtau10 + 16 and 13 controls). Results: Bulk tissue RNA sequencing reveals substantial downregulation of gene expression associated with synaptic function. Upregulated biological pathways in human MAPT 10 + 16 brain included those involved in transcriptional regulation, DNA damage response and neuroinflammation. Histopathology confirmed increased pathological tau accumulation in FTDtau10 + 16 cortex as well as a loss of presynaptic protein staining and region‐specific increased colocalization of phospho‐tau with synapses in temporal cortex. Conclusions: Our data indicate that synaptic pathology likely contributes to pathogenesis in FTDtau10 + 16 caused by the MAPT 10 + 16 mutation. [ABSTRACT FROM AUTHOR]

Immunoglobulin Mu‐binding protein 2 (IGHMBP2) pathogenic variants result in the fatal, neurodegenerative disease spinal muscular atrophy with respiratory distress type 1 (SMARD1) and the milder, Charcot–Marie‐Tooth (CMT) type 2S (CMT2S) neuropathy. More than 20 years after the link between IGHMBP2 and SMARD1 was revealed, and 10 years after the discovery of the association between IGHMBP2 and CMT2S, the pathogenic mechanism of these diseases is still not well defined. The discovery that IGHMBP2 functions as an RNA/DNA helicase was an important step, but it did not reveal the pathogenic mechanism. Helicases are enzymes that use ATP hydrolysis to catalyse the separation of nucleic acid strands. They are involved in numerous cellular processes, including DNA repair and transcription; RNA splicing, transport, editing and degradation; ribosome biogenesis; translation; telomere maintenance; and homologous recombination. IGHMBP2 appears to be a multifunctional factor involved in several cellular processes that regulate gene expression. It is difficult to determine which processes, when dysregulated, lead to pathology. Here, we summarise our current knowledge of the clinical presentation of IGHMBP2‐related diseases. We also overview the available models, including yeast, mice and cells, which are used to study the function of IGHMBP2 and the pathogenesis of the related diseases. Further, we discuss the structure of the IGHMBP2 protein and its postulated roles in cellular functioning. Finally, we present potential anomalies that may result in the neurodegeneration observed in IGHMBP2‐related disease and highlight the most prominent ones. [ABSTRACT FROM AUTHOR]

Background: Mutations in several translation initiation factors are closely associated with premature ovarian insufficiency (POI), but the underlying pathogenesis remains largely unknown. Methods and results: We generated eukaryotic translation initiation factor 5 (Eif5) conditional knockout mice aiming to investigate the function of eIF5 during oocyte growth and follicle development. Here, we demonstrated that Eif5 deletion in mouse primordial and growing oocytes both resulted in the apoptosis of oocytes within the early‐growing follicles. Further studies revealed that Eif5 deletion in oocytes downregulated the levels of mitochondrial fission‐related proteins (p‐DRP1, FIS1, MFF and MTFR) and upregulated the levels of the integrated stress response‐related proteins (AARS1, SHMT2 and SLC7A1) and genes (Atf4, Ddit3 and Fgf21). Consistent with this, Eif5 deletion in oocytes resulted in mitochondrial dysfunction characterized by elongated form, aggregated distribution beneath the oocyte membrane, decreased adenosine triphosphate content and mtDNA copy numbers, and excessive accumulation of reactive oxygen species (ROS) and mitochondrial superoxide. Meanwhile, Eif5 deletion in oocytes led to a significant increase in the levels of DNA damage response proteins (γH2AX, p‐CHK2 and p‐p53) and proapoptotic proteins (PUMA and BAX), as well as a significant decrease in the levels of anti‐apoptotic protein BCL‐xL. Conclusion: These findings indicate that Eif5 deletion in mouse oocytes results in the apoptosis of oocytes within the early‐growing follicles via mitochondrial fission defects, excessive ROS accumulation and DNA damage. This study provides new insights into pathogenesis, genetic diagnosis and potential therapeutic targets for POI. Key points: Eif5 deletion in oocytes leads to arrest in oocyte growth and follicle development.Eif5 deletion in oocytes impairs the translation of mitochondrial fission‐related proteins, followed by mitochondrial dysfunction.Depletion of Eif5 causes oocyte apoptosis via ROS accumulation and DNA damage response pathway. [ABSTRACT FROM AUTHOR]

This article discusses a study that examines the relationship between whole-genome doubling (WGD) and different types of cancer. The study analyzes data from 10 cancer types and identifies three types of WGD tumors. The researchers also identify specific genetic signatures associated with WGD in different types of cancer and suggest potential therapeutic targets for WGD tumors. The study was supported by grants and the authors have no conflicts of interest. Further research is needed to evaluate the effectiveness of these targeted therapies. [Extracted from the article]

The aggressive characteristics of triple‐negative breast cancer (TNBC) and the absence of targeted medicines make TNBC a challenging clinical case. The molecular landscape of TNBC has been well‐understood thanks to recent developments in multi‐omic analysis, which have also revealed dysregulated pathways and possible treatment targets. This review summarizes the utilization of multi‐omic approaches in elucidating TNBC's complex biology and therapeutic avenues. Dysregulated pathways including cell cycle progression, immunological modulation, and DNA damage response have been uncovered in TNBC by multi‐omic investigations that integrate genomes, transcriptomics, proteomics, and metabolomics data. Methods like this pave the door for the discovery of new therapeutic targets, such as the EGFR, PARP, and mTOR pathways, which in turn direct the creation of more precise treatments. Recent developments in TNBC treatment strategies, including immunotherapy, PARP inhibitors, and antibody‐drug conjugates, show promise in clinical trials. Emerging biomarkers like MUC1, YB‐1, and immune‐related markers offer insights into personalized treatment approaches and prognosis prediction. Despite the strengths of multi‐omic analysis in offering a more comprehensive view and personalized treatment strategies, challenges exist. Large sample sizes and ensuring high‐quality data remain crucial for reliable findings. Multi‐omic analysis has revolutionized TNBC research, shedding light on dysregulated pathways, potential targets, and emerging biomarkers. Continued research efforts are imperative to translate these insights into improved outcomes for TNBC patients. [ABSTRACT FROM AUTHOR]

Human papillomaviruses (HPVs) are non‐enveloped double‐stranded DNA viruses. When HPV infection persists, infected tissues can develop many HPV‐related diseases such as cervical cancer and head and neck squamous cell carcinoma. To establish their persistent infection, HPVs have evolved mechanisms to manipulate the host cellular processes such as DNA damage response (DDR), which includes homologous recombination, nonhomologous end joining, and microhomology‐mediated end joining. Additionally, HPVs utilize host inflammatory processes to facilitate their life cycles. Here, we bridge the concepts of DDR and inflammatory response, and discuss how HPV proteins orchestrate a sophisticated manipulation of DDR and inflammation to promote their viral replication, ultimately fostering the progression of infected cells towards oncogenic transformation to malignancy. [ABSTRACT FROM AUTHOR]

Thyroid cancer incidence increases worldwide annually, primarily due to factors such as ionizing radiation (IR), iodine intake, and genetics. Papillary carcinoma of the thyroid (PTC) accounts for about 80% of thyroid cancer cases. RET/PTC1 (coiled‐coil domain containing 6 [CCDC6]‐rearranged during transfection) rearrangement is a distinctive feature in over 70% of thyroid cancers who exposed to low doses of IR in Chernobyl and Hiroshima‒Nagasaki atomic bombings. This study aims to elucidate mechanism between RET/PTC1 rearrangement and IR in PTC. N‐thy‐ori‐3‐1 cells were subjected to varying doses of IR (2/1/0.5/0.2/0.1/0.05 Gy) of IR at different days, and result showed low‐dose IR‐induced RET/PTC1 rearrangement in a dose‐dependent manner. RET/PTC1 has been observed to promote PTC both in vivo and in vitro. To delineate the role of different DNA repair pathways, SCR7, RI‐1, and Olaparib were employed to inhibit non‐homologous end joining (NHEJ), homologous recombination (HR), and microhomology‐mediated end joining (MMEJ), respectively. Notably, inhibiting NHEJ enhanced HR repair efficiency and reduced IR‐induced RET/PTC1 rearrangement. Conversely, inhibiting HR increased NHEJ repair efficiency and subsequent RET/PTC1 rearrangement. The MMEJ did not show a markable role in this progress. Additionally, inhibiting DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs) decreased the efficiency of NHEJ and thus reduced IR‐induced RET/PTC1 rearrangement. To conclude, the data suggest that NHEJ, rather than HR or MMEJ, is the critical cause of IR‐induced RET/PTC1 rearrangement. Targeting DNA‐PKcs to inhibit the NHEJ has emerged as a promising therapeutic strategy for addressing IR‐induced RET/PTC1 rearrangement in PTC. [ABSTRACT FROM AUTHOR]

DNA damage is a prevalent phenomenon in the context of cancer progression. Evidence suggests that DNA damage responses (DDR) are pivotal in overcoming tumor immune evasion. Alternatively, traditional radiotherapy and chemotherapy operate by inducing DNA damage, consequently stimulating the immune system to target tumors. The intricate interplay between signaling pathways involved in DDR and immune activation underscores the significance of considering both factors in developing improved immunotherapies. By delving deeper into the mechanisms underlying immune activation brought on by DNA damage, it becomes possible to identify novel treatment approaches that boost the anticancer immune response while minimizing undesirable side effects. This review explores the mechanisms behind DNA damage‐induced antitumor immune responses, the importance of DNA damage in antitumor immunity, and potential therapeutic approaches for cancer immunotherapy targeting DDR. Additionally, we discuss the challenges of combination therapy and strategies for integrating DNA damage‐targeting therapies with current cancer immunotherapy. In summary, this review highlights the critical role of DNA damage in tumor immunology, underscoring the potential of DDR inhibitors as promising therapeutic modalities for cancer treatment. [ABSTRACT FROM AUTHOR]

SUMMARY With the advancement of CRISPR technologies, a comprehensive understanding of repair mechanisms following double‐strand break (DSB) formation is important for improving the precision and efficiency of genetic modifications. In plant genetics, two Cas nucleases are widely used, i.e. Cas9 and Cas12a, which differ with respect to PAM sequence composition, position of the DSB relative to the PAM, and DSB‐end configuration (blunt vs. staggered). The latter difference has led to speculations about different options for repair and recombination. Here, we provide detailed repair profiles for LbCas12a in Arabidopsis thaliana, using identical experimental settings previously reported for Cas9‐induced DSBs, thus allowing for a quantitative comparison of both nucleases. For both enzymes, non‐homologous end‐joining (NHEJ) produces 70% of mutations, whereas polymerase theta‐mediated end‐joining (TMEJ) generates 30%, indicating that DSB‐end configuration does not dictate repair pathway choice. Relevant for genome engineering approaches aimed at integrating exogenous DNA, we found that Cas12a similarly stimulates the integration of T‐DNA molecules as does Cas9. Long‐read sequencing of both Cas9 and Cas12a repair outcomes further revealed a previously underappreciated degree of DNA loss upon TMEJ. The most notable disparity between Cas9 and Cas12a repair profiles is caused by how NHEJ acts on DSB ends with short overhangs: non‐symmetric Cas9 cleavage produce 1 bp insertions, which we here show to depend on polymerase Lambda, whereas staggered Cas12a DSBs are not subjected to fill‐in synthesis. We conclude that Cas9 and Cas12a are equally effective for genome engineering purposes, offering flexibility in nuclease choice based on the availability of compatible PAM sequences. [ABSTRACT FROM AUTHOR]

Eukaryotic translation initiation factor 2 subunit 2 (EIF2S2), a subunit of the heterotrimeric G protein EIF2, is involved in the initiation of translation. Our findings demonstrate that the depletion of Eif2s2 in premeiotic germ cells causes oocyte arrest at the pachytene and early diplotene stages at 1 day postpartum (dpp) and 5 dpp, respectively, and eventually leads to oocyte apoptosis and failure of primordial follicle formation. Further studies reveal that Eif2s2 deletion downregulates homologous recombination‐related and mitochondrial fission‐related protein levels, and upregulates the integrated stress response‐related proteins and mRNA levels. Consistently, Eif2s2 deletion significantly decreases the expression of dictyate genes and compromises mitochondrial function, characterized by elongated shapes, decreased ATP levels and mtDNA copy number, along with an excessive accumulation of reactive oxygen species (ROS) and mitochondrial superoxide. Furthermore, DNA damage response and proapoptotic protein levels increase, while anti‐apoptotic protein levels decrease in Eif2s2‐deleted mice. An increase in oocytes with positive cleaved‐Caspase‐3 and TUNEL signals, alongside reduced Lamin B1 intensity, further indicates oocyte apoptosis. Collectively, Eif2s2 deletion in premeiotic germ cells causes oocyte meiotic arrest at the early diplotene stage by impairing homologous recombination, and eventually leads to oocyte apoptosis mainly through the downregulation of mitochondrial fission‐related proteins, ROS accumulation and subsequent DNA damage. [ABSTRACT FROM AUTHOR]

DNA damage plays a significant role in the tumorigenesis and progression of the disease. Abnormal DNA repair affects the therapy and prognosis of cancer. In this study, it is demonstrated that the deubiquitinase USP25 promotes non‐homologous end joining (NHEJ), which in turn contributes to chemoresistance in cancer. It is shown that USP25 deubiquitinates SHLD2 at the K64 site, which enhances its binding with REV7 and promotes NHEJ. Furthermore, USP25 deficiency impairs NHEJ‐mediated DNA repair and reduces class switch recombination (CSR) in USP25‐deficient mice. USP25 is overexpressed in a subset of colon cancers. Depletion of USP25 sensitizes colon cancer cells to IR, 5‐Fu, and cisplatin. TRIM25 is also identified, an E3 ligase, as the enzyme responsible for degrading USP25. Downregulation of TRIM25 leads to an increase in USP25 levels, which in turn induces chemoresistance in colon cancer cells. Finally, a peptide that disrupts the USP25‐SHLD2 interaction is successfully identified, impairing NHEJ and increasing sensitivity to chemotherapy in PDX model. Overall, these findings reveal USP25 as a critical effector of SHLD2 in regulating the NHEJ repair pathway and suggest its potential as a therapeutic target for cancer therapy. [ABSTRACT FROM AUTHOR]

In the early embryonic stages, Lin‐28 homologue A (Lin28a) is highly expressed and declines as the embryo matures. As an RNA‐binding protein, Lin28a maintains some adult muscle stem cells (MuSCs) in an embryonic‐like state, but its RNA metabolism regulation mechanism remains unclear. BioGPS analysis revealed that Lin28a expression is significantly higher in muscle tissues than in other tissues. Lin28a‐positive muscle stem cells (Lin28a+ MuSCs) were sorted from Lin28a‐CreERT2; LSL‐tdTomato mouse skeletal muscle tissue, which exhibited a higher proliferation rate than the control group. Lin28a‐bound transcripts are enriched in various biological processes such as DNA repair, cell cycle, mitochondrial tricarboxylic acid cycle and oxidative stress response. The expression of insulin‐like growth factor 2 mRNA‐binding protein 3 (Igf2bp3) was markedly elevated in the presence of Lin28a. Co‐immunoprecipitation analysis further demonstrated that Lin28a associates with Igf2bp3. Immunofluorescence analyses confirmed that Lin28a, Igf2bp3 and G3bp1 colocalize to form stress granules (SG), and N6‐methyladenosine (m6A) modification promotes the formation of Lin28a‐SG. Sequencing of the transcriptome and RNAs immunoprecipitated by Lin28a, Igf2bp3 and m6A antibodies in Lin28a+ MuSCs further revealed that Lin28a and Igf2bp3 collaboratively regulate the expression of DNA repair‐related genes, including Fancm and Usp1. Lin28a stabilises Igf2bp3, Usp1, and Fancm mRNAs, enhancing DNA repair against oxidative or proteotoxic stress, thus promoting MuSCs self‐renewal. Understanding the intricate mechanisms through which Lin28a and Igf2bp3 regulate MuSCs provides a deeper understanding of stem cell self‐renewal, with potential implications for regenerative medicine. [ABSTRACT FROM AUTHOR]

Aluminum‐dependent stoppage of root growth requires the DNA damage response (DDR) pathway including the p53‐like transcription factor SUPPRESSOR OF GAMMA RADIATION 1 (SOG1), which promotes terminal differentiation of the root tip in response to Al dependent cell death. Transcriptomic analyses identified Al‐induced SOG1‐regulated targets as candidate mediators of this growth arrest. Analysis of these factors either as loss‐of‐function mutants or by overexpression in the als3‐1 background shows ERF115, which is a key transcription factor that in other scenarios is rate‐limiting for damaged stem cell replenishment, instead participates in transition from an actively growing root to one that has terminally differentiated in response to Al toxicity. This is supported by a loss‐of‐function erf115 mutant raising the threshold of Al required to promote terminal differentiation of Al hypersensitive als3‐1. Consistent with its key role in stoppage of root growth, a putative ERF115 barley ortholog is also upregulated following Al exposure, suggesting a conserved role for this ATR‐dependent pathway in Al response. In contrast to other DNA damage agents, these results show that ERF115 and likely related family members are important determinants of terminal differentiation of the root tip following Al exposure and central outputs of the SOG1‐mediated pathway in Al response. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are associated with oocyte maturation inhibition, and N‐acetyl‐l‐cysteine (NAC) partially reduces their harmful effects. Mitochondrial E3 ubiquitin ligase 1 (Mul1) localizes to the mitochondrial outer membrane. We found that female Mul1‐deficient mice are infertile, and their oocytes contain high ROS concentrations. After fertilization, Mul1‐deficient embryos showed a DNA damage response (DDR) and abnormal preimplantation embryogenesis, which was rescued by NAC addition and ROS depletion. These observations clearly demonstrate that loss of Mul1 in oocytes increases ROS concentrations and triggers DDR, resulting in abnormal preimplantation embryogenesis. We conclude that manipulating the mitochondrial ROS levels in oocytes may be a potential therapeutic approach to target infertility. [ABSTRACT FROM AUTHOR]

Microproteins, known as micropeptides, are small protein molecules encoded by short open reading frames. These recently identified molecules have been proven to be an essential part of the human proteome that participates in multiple processes, such as DNA repair, mitochondrial respiration, and regulating different signaling pathways. A growing body of studies has evidenced that microproteins exhibit dysregulated expression levels in various malignancies and contribute to tumor progression. It has been reported that microproteins interact with many proteins, such as enzymes (e.g., adenosine triphosphate synthase) and signal transducers (e.g., c‐Jun), and regulate malignant cell metabolism, proliferation, and metastasis. Moreover, microproteins have been found to play a significant role in multidrug resistance in vitro and in vivo by their activity in DNA repair pathways. Considering that, this review intended to summarize the roles of microproteins in different aspects of tumorigenesis with diagnostic and therapeutic perspectives. [ABSTRACT FROM AUTHOR]

This review discusses the less‐explored realm of DNA damage and repair within the enteric nervous system (ENS), often referred to as the “second brain.” While the central nervous system has been extensively studied for its DNA repair mechanisms and associated neuropathologies, the ENS, which can autonomously coordinate gastrointestinal function, experiences unique challenges and vulnerabilities related to its genome integrity. The susceptibility of the ENS to DNA damage is exacerbated by its limited protective barriers, resulting in not only endogenous genotoxic exposures, such as oxidative stress, but also exogenous threats, such as ingested environmental contaminants, local inflammatory responses, and gut dysbiosis. Here, we discuss the evidence for DNA repair defects in enteric neuropathies, most notably, the reported relationship between inherited mutations in RAD21 and LIG3 with chronic intestinal pseudo‐obstruction and mitochondrial gastrointestinal encephalomyopathy disorders, respectively. We also introduce the lesser‐recognized gastrointestinal complications in DNA repair syndromes, including conditions like Cockayne syndrome. The review concludes by pointing out the potential role of DNA repair defects in not only congenital disorders but also aging‐related gut dysfunction, as well as the crucial need for further research to establish direct causal links between DNA damage accumulation and ENS‐specific pathologic phenotypes. [ABSTRACT FROM AUTHOR]

MCM8 has emerged as a core gene in reproductive aging and is crucial for meiotic homologous recombination repair. It also safeguards genome stability by coordinating the replication stress response during mitosis, but its function in mitotic germ cells remains elusive. Here we found that disabling MCM8 in mice resulted in proliferation defects of primordial germ cells (PGCs) and ultimately impaired fertility. We further demonstrated that MCM8 interacted with two known helicases DDX5 and DHX9, and loss of MCM8 led to R-loop accumulation by reducing the retention of these helicases at R-loops, thus inducing genome instability. Cells expressing premature ovarian insufficiency-causative mutants of MCM8 with decreased interaction with DDX5 displayed increased R-loop levels. These results show MCM8 interacts with R-loop-resolving factors to prevent R-loop-induced DNA damage, which may contribute to the maintenance of genome integrity of PGCs and reproductive reserve establishment. Our findings thus reveal an essential role for MCM8 in PGC development and improve our understanding of reproductive aging caused by genome instability in mitotic germ cells. Synopsis: MCM8 deficiency impairs meiotic homologous recombination repair, but the specific role of MCM8 in mitotic germ cells remains poorly understood. This study reveals that MCM8 interacts with helicase DDX5 to prevent R-loop-induced DNA damage, and maintains primordial germ cell (PGC) genome stability and rapid proliferation. MCM8 safeguards PGC rapid proliferation to establish reproductive reserve. MCM8 retains DDX5 at R-loops to prevent R-loop-induced DNA damage. MCM8 mutations associated with premature ovarian insufficiency (POI) affect interactions with DDX5 and increase R-loop levels. Loss of MCM8 compromises primordial germ cell proliferation in mice, possibly via DNA damage caused by reduced retention of R-loop-resolving factors. [ABSTRACT FROM AUTHOR]

Low‐dose 5‐aminolevulinic acid photodynamic therapy (ALA‐PDT) has been used to cope with skin photoaging, and is thought to involve DNA damage repair responses. However, it is still unknown how low‐dose ALA‐PDT regulates DNA damage repair to curb skin photoaging. We established a photoaging model using human dermal fibroblasts (HDFs) and rat skin. RNA‐sequencing (RNA‐seq) analysis was conducted to identify differentially expressed genes (DEGs) in HDFs before and after low‐dose ALA‐PDT treatment, followed by bioinformatics analysis. Senescence‐associated β‐galactosidase (SA‐β‐gal) staining was employed to assess skin aging‐related manifestations and Western blotting to evaluate the expression of associated proteins. A comet assay was used to detect cellular DNA damage, while immunofluorescence to examine the expression of 8‐hydroxy‐2′‐deoxyguanosine (8‐oxo‐dG) in cells and skin tissues. In both in vivo and in vitro models, low‐dose ALA‐PDT alleviated the manifestations of ultraviolet B (UVB)‐induced skin photoaging. Low‐dose ALA‐PDT significantly reduced DNA damage in photoaged HDFs. Furthermore, low‐dose ALA‐PDT accelerated the clearance of the photoproduct 8‐oxo‐dG in photoaged HDFs and superficial dermis of photoaged rat skin. RNA‐seq analysis suggested that low‐dose ALA‐PDT upregulated the expression of key genes in the base excision repair (BER) pathway. Further functional validation showed that inhibition on BER expression by using UPF1069 significantly suppressed SA‐β‐gal activity, G2/M phase ratio, expression of aging‐associated proteins P16, P21, P53, and MUTYH proteins, as well as clearance of the photoproduct 8‐oxo‐dG in photoaged HDFs. Low‐dose ALA‐PDT exerts anti‐photoaging effects by activating the BER signalling pathway. [ABSTRACT FROM AUTHOR]

The effects of genotoxic agents on DNA and the processes involved in their removal have been thoroughly studied; however, very little is known about the mechanisms governing the reinstatement of cellular activities after DNA repair, despite restoration of the damage‐induced block of transcription being essential for cell survival. In addition to impeding transcription, DNA lesions have the potential to disrupt the precise positioning of chromatin domains within the nucleus and alter the meticulously organized architecture of the nucleolus. Alongside the necessity of resuming transcription mediated by RNA polymerase 1 and 2 transcription, it is crucial to restore the structure of the nucleolus to facilitate optimal ribosome biogenesis and ensure efficient and error‐free translation. Here, we examine the current understanding of how transcriptional activity from RNA polymerase 2 is reinstated following DNA repair completion and explore the mechanisms involved in reassembling the nucleolus to safeguard the correct progression of cellular functions. Given the lack of information on this vital function, this Review seeks to inspire researchers to explore deeper into this specific subject and offers essential suggestions on how to investigate this complex and nearly unexplored process further. [ABSTRACT FROM AUTHOR]

It is newly revealed that collagen works as a physical barrier to tumor immune infiltration, oxygen perfusion, and immune depressor in solid tumors. Meanwhile, after radiotherapy (RT), the programmed death ligand‐1 (PD‐L1) overexpression and transforming growth factor‐β (TGF‐β) excessive secretion would accelerate DNA damage repair and trigger T cell exclusion to limit RT efficacy. However, existing drugs or nanoparticles can hardly address these obstacles of highly effective RT simultaneously, effectively, and easily. In this study, it is revealed that inducing mitochondria dysfunction by using oxidative phosphorylation inhibitors like Lonidamine (LND) can serve as a highly effective multi‐immune pathway regulation strategy through PD‐L1, collagen, and TGF‐β co‐depression. Then, IR‐LND is prepared by combining the mitochondria‐targeted molecule IR‐68 with LND, which then is loaded with liposomes (Lip) to create IR‐LND@Lip nanoadjuvants. By doing this, IR‐LND@Lip more effectively sensitizes RT by generating more DNA damage and transforming cold tumors into hot ones through immune activation by PD‐L1, collagen, and TGF‐β co‐inhibition. In conclusion, the combined treatment of RT and IR‐LND@Lip ultimately almost completely suppressed the growth of bladder tumors and breast tumors. [ABSTRACT FROM AUTHOR]