Maintaining Genome Integrity Research Articles

Extensive homologous recombinationsafeguards oocyte genome integrity in mammals.

Meiosis in mammalian oocytes is interrupted by a prolonged arrest at the germinal vesiclestage, during which oocytes have to repair DNA lesions to ensure genome integrityor otherwise undergo apoptosis. The FIRRM/FLIP-FIGNL1 complex dissociates RAD51 from the joint DNA molecules in both homologous recombination (HR) and DNA replication. However, as a type of non-meiotic, non-replicative cells, whether this RAD51-dismantling mechanism regulates genome integrity in oocytes remains elusive. Here, we show that FIRRM/FLIP is required for disassembly of RAD51-filaments and maintenance of genome integrity in oocytes. Deletion of FIRRM in oocytes leads to formation of massive nuclear RAD51 foci in oocytes of primordial follicles and activated follicles in mice. These RAD51 foci colocalize with the sites of DNA damage repair, as indicated by RPA2 and EdU, suggesting substantial DNA damage and extensive HR in oocytes. Especially in fully-grown FIRRM-deleted oocytes, RAD51 forms a net-like structure. As a consequence, FIRRM-deleted females are infertile due to aberrant homologous chromosome segregation at metaphase I and primordial follicle insufficiency at young adulthood. Hence, our study demonstrates the physiological importance of HR in maintaining genome integrity in oocytes.

Beyond Nucleotide Excision Repair: The Importance of XPF in Base Excision Repair and Its Impact on Cancer, Inflammation, and Aging.

DNA repair involves various intricate pathways that work together to maintain genome integrity. XPF (ERCC4) is a structural endonuclease that forms a heterodimer with ERCC1 that is critical in both single-strand break repair (SSBR) and double-strand break repair (DSBR). Although the mechanistic function of ERCC1/XPF has been established in nucleotide excision repair (NER), its role in long-patch base excision repair (BER) has recently been discovered through the 5'-Gap pathway. This study briefly explores the roles of XPF in different pathways to emphasize the importance of XPF in DNA repair. XPF deficiency manifests in various diseases, including cancer, neurodegeneration, and aging-related disorders; it is also associated with conditions such as Xeroderma pigmentosum and fertility issues. By examining the molecular mechanisms and pathological consequences linked to XPF dysfunction, this study aims to elucidate the crucial role of XPF in genomic stability as a repair protein in BER and provide perspectives regarding its potential as a therapeutic target in related diseases.

A complete DNA repair system assembled by two endosymbionts restores heat tolerance of the insect host

DNA repair systems are essential to maintain genome integrity and stability. Some obligate endosymbionts that experience long-term symbiosis with the insect hosts, however, have lost their key components for DNA repair. It is largely unexplored how the bacterial endosymbionts cope with the increased demand for mismatch repairs under heat stresses. Here, we showed that ibpA, a small heat shock protein encoded by Buchnera aphidicola, directly interacted with the cytoskeletal actin to prevent its aggregation in bacteriocytes, thus reinforcing the stability of bacteriocytes. However, the succession of 11 adenines in the promoter of ibpA is extremely prone to mismatching error, e.g., a single adenine deletion, which impairs the induction of ibpA under heat stress. Coinfection with a facultative endosymbiont Serratia symbiotica remarkably reduced the mutagenesis rate in the Buchnera genome and potentially prevented a single adenine deletion in ibpA promoter, thereby alleviating the heat vulnerability of aphid bacteriocytes. Furthermore, Serratia encoded mutH, a conserved core protein of prokaryotic DNA mismatch repair (MMR), accessed to Buchnera cells, which complemented Buchnera mutL and mutS in constituting an active MMR. Our findings imply that a full complement of a prokaryotic MMR system assembled by two bacterial endosymbionts contributes significantly to the thermostability of aphid bacteriocytes in an ibpA-dependent manner, furnishing a distinct molecular link among tripartite symbioses in shaping resilience and adaptation of their insect hosts to occupy other ecological niches.

Influence of aging and maternal protein restriction on PIWI-interacting RNA expression in the offspring rat ventral prostate

The Developmental Origins of Health and Disease (DOHaD) concept explores the link between exposure to adverse conditions during fetal and early childhood development and the onset of chronic non-communicable diseases, such as prostate cancer (PCa). Changes in epigenetics that control gene expression have been identified as potential contributors to the developmental origin of PCa. Piwi-interacting RNAs (piRNAs), for example, control transposable elements (TEs) and maintain genome integrity in germ cells. However, stress-induced deregulation of TEs warrants investigating the role of piRNAs in the prostate gland from the DOHaD perspective, which remains underexplored. This study aimed to detect and characterize piRNA expression in the ventral prostate (VP) of Sprague Dawley rat offspring at 21 postnatal days (PND21) and PND540. The rats were subjected to maternal protein restriction during pregnancy and lactation to understand its impact on prostate development and aging. Histological analyses showed that the gestational and lactation low-protein diet (GLLP) group experienced a delay in prostate gland development, with increased stromal and epithelial compartments and decreased luminal compartments during early life. Aging in this group resulted in decreased luminal compartments and increased stromal areas. Epithelial atrophy was observed in both groups, with an increased incidence of carcinoma in situ in the GLLP group. Small RNA sequencing from control and restricted groups (at PND21 and PND540) identified piRNA clusters in both young and aged animals. We also detected the expression of PIWI genes (Riwi, Rili, Rili2) in the prostate. Our data highlight the key role of maternal malnutrition in modulating piRNA expression in the offspring’s VP, with the potential to influence prostate developmental biology and the risk of prostatic disorders with aging.

Molecular basis of FIGNL1 in dissociating RAD51 from DNA and chromatin.

Maintaining genome integrity is an essential and challenging process. RAD51 recombinase, the central player of several crucial processes in repairing DNA and protecting genome integrity, forms filaments on DNA, which are tightly regulated. One of these RAD51 regulators is FIGNL1, that prevents persistent RAD51 foci without or after DNA damage and genotoxic chromatin association in cells. The cryogenic electron microscopy structure of FIGNL1 in complex with RAD51 reveals that FIGNL1 forms a non-planar hexamer and RAD51 N terminus enclosure in the FIGNL1 hexamer pore. Mutations in pore loop or catalytic residues of FIGNL1 render it defective in filament disassembly and are lethal in mouse embryonic stem cells. Our study reveals a unique mechanism for removing RAD51 from bound substrates and provides the molecular basis for FIGNL1 in maintaining genome stability.

CCDC69 maintains genome integrity by regulating KIF2C/MCAK depolymerase activity and the stability of the chromosomal passenger complex

Accurate genome inheritance during cell division relies on a complex chromosome segregation mechanism. This process occurs once all the kinetochores of sister chromatids are attached to microtubules emanating from the opposite poles of the mitotic spindle. To control the precision of this mechanism, the Chromosome Passenger Complex (CPC) actively identifies and corrects improper microtubule attachments. The depolymerase activity of the kinesin KIF2C/MCAK at the kinetochores is involved in this process. CCDC69 is a poorly characterized protein, primarily identified as a regulator of central spindle assembly, whose overexpression prompts rapid microtubule depolymerization. Here, we show that CCDC69 is a cell-cycle regulated protein belonging to the Microtubule-associated Tumor Suppressor (MTUS) superfamily, and even slight deregulation of its expression induces severe early mitotic phenotypes. Myristoylation anchors CCDC69 at the plasma membrane, thus protecting microtubule network integrity. We found that CCDC69 microtubule depolymerization activity relies on KIF2C, with a fraction of CCDC69 localizing to the centromere. Importantly, we demonstrated that CCDC69 regulates the stability of the CPC by safeguarding its members from degradation during mitosis. In summary, our findings underscore CCDC69’s essential role as a mitotic regulator, which is crucial for maintaining the fidelity of chromosome segregation.

Unraveling the Guardian: p53's Multifaceted Role in the DNA Damage Response and Tumor Treatment Strategies.

DNA damage can lead to mutations that can alter the function of oncogenes or tumor suppressor genes, thus promoting the development of cancer. p53 plays a multifaceted and complex role in the DNA damage response and cancer progression and is known as the 'guardian of the gene'. When DNA damage occurs, p53 is activated through a series of post-translational modifications, which stabilize the protein and enhance its function as a transcription factor. It regulates processes including cell cycle checkpoints, DNA repair and apoptosis, thereby preventing the spread of damaged DNA and maintaining genome integrity. On the one hand, p53 can initiate cell cycle arrest and induce cells to enter the G1/S and G2/M checkpoints, preventing cells with damaged DNA from continuing to proliferate and gaining time for DNA repair. At the same time, p53 can promote the activation of DNA repair pathways, including base excision repair, nucleotide excision repair and other repair pathways, to ensure the integrity of genetic material. If the damage is too severe to repair, p53 will trigger the apoptosis process to eliminate potential cancer risks in time. p53 also plays a pivotal role in cancer progression. Mutations in the p53 gene are frequently found in many cancers, and the mutated p53 not only loses its normal tumor suppressor function but may even acquire pro-cancer activity. Therefore, we also discuss therapeutic strategies targeting the p53 pathway, such as the use of small-molecule drugs to restore the function of wild-type p53, the inhibition of negative regulatory factors and synthetic lethality approaches for p53-deficient tumors. This review therefore highlights the important role of p53 in maintaining genomic stability and its potential in therapeutic strategies for cancer.

Characterization of radiations-induced genomic structural variations in Arabidopsis thaliana.

DNA, is assaulted by endogenous and exogenous agents that lead to the formation of damage. In order to maintain genome integrity DNA repair pathways must be efficiently activated to prevent mutations and deleterious chromosomal rearrangements. Conversely, genome rearrangement is also necessary to allow genetic diversity and evolution. The antagonist interaction between maintenance of genome integrity and rearrangements determines genome shape and organization. Therefore, it is of great interest to understand how the whole linear genome structure behaves upon formation and repair of DNA damage. For this, we used long reads sequencing technology to identify and to characterize genomic structural variations (SV) of wild-type Arabidopsis thaliana somatic cells exposed either to UV-B, to UV-C or to protons irradiations. We found that genomic regions located in heterochromatin are more prone to form SVs than those located in euchromatin, highlighting that genome stability differs along the chromosome. This holds true in Arabidopsis plants deficient for the expression of master regulators of the DNA damage response (DDR), ATM (Ataxia-telangiectasia-mutated) and ATR (Ataxia-telangiectasia-mutated and Rad3-related), suggesting that independent and alternative surveillance processes exist to maintain integrity in genic regions. Finally, the analysis of the radiations-induced deleted regions allowed determining that exposure to UV-B, UV-C and protons induced the microhomology-mediated end joining mechanism (MMEJ) and that both ATM and ATR repress this repair pathway.

A systematic quantitative approach comprehensively defines domain-specific functional pathways linked to Schizosaccharomyces pombe heterochromatin regulation.

Heterochromatin plays a critical role in regulating gene expression and maintaining genome integrity. While structural and enzymatic components have been linked to heterochromatin establishment, a comprehensive view of the underlying pathways at diverse heterochromatin domains remains elusive. Here, we developed a systematic approach to identify factors involved in heterochromatin silencing at pericentromeres, subtelomeres and the silent mating type locus in Schizosaccharomyces pombe. Using quantitative measures, iterative genetic screening and domain-specific heterochromatin reporters, we identified 369 mutants with different degrees of reduced or enhanced silencing. As expected, mutations in the core heterochromatin machinery globally decreased silencing. However, most other mutants exhibited distinct qualitative and quantitative profiles that indicate heterochromatin domain-specific functions, as seen for example for metabolic pathways affecting primarily subtelomere silencing. Moreover, similar phenotypic profiles revealed shared functions for subunits within complexes. We further discovered that the uncharacterized protein Dhm2 plays a crucial role in heterochromatin maintenance, affecting the inheritance of H3K9 methylation and the clonal propagation of the repressed state. Additionally, Dhm2 loss resulted in delayed S-phase progression and replication stress. Collectively, our systematic approach unveiled a landscape of domain-specific heterochromatin regulators controlling distinct states and identified Dhm2 as a previously unknown factor linked to heterochromatin inheritance and replication fidelity.

Histone H3 N-terminal recognition by the PHD finger of PHRF1 is required for proper DNA damage response.

Plant homeodomain (PHD) fingers are critical effectors of histone post-translational modifications (PTMs), acting as regulators of gene expression and genome integrity, and frequently presenting in human disease. While most PHD fingers recognize unmodified and methylated states of histone H3 lysine 4 (H3K4), the specific functions of many of the over 100 PHD finger-containing proteins in humans remain poorly understood, despite their significant implications in disease processes. In this study, we undertook a comprehensive analysis of one such poorly characterized PHD finger-containing protein, PHRF1. Using biochemical, molecular, and cellular approaches, we show that PHRF1 robustly binds to histone H3, specifically at its N-terminal region. Through RNA-seq and proteomic analyses, we also find that PHRF1 is intricately involved in transcriptional and RNA splicing regulation and plays a significant role in DNA damage response (DDR). Crucially, mutagenesis of proline 221 to leucine (P221L) in the PHD finger of PHRF1 abolishes histone interaction and fails to rescue defective DDR. These findings underscore the importance of PHRF1-H3 interaction in maintaining genome integrity and provide insight into how PHD fingers contribute to chromatin biology.

Biochemical, structural, and single-molecule characterization of LIG1 active site mutants demonstrate role of F635 and F872 residues for faithful ligation.

Human DNA ligase 1 (LIG1) finalizes DNA repair pathways by an ultimate ligation step and discriminates against nicks containing unusual ends, yet the contribution of the conserved active site residues for faithful end joining remains unknown. Here, using biochemistry, X-ray crystallography, and single-molecule approaches, we comprehensively characterized LIG1 mutants carrying Ala(A) and Leu(L) substitutions at the active site residues Phe(F)635 and Phe(F)872. Our results showed an abolished ligation of nick DNA substrates with all 12 non-canonical mismatches, while the mutagenic nick sealing of oxidatively damaged ends by wild-type enzyme is significantly reduced by F635A/L and F872A/L substitutions. Furthermore, sugar discrimination against a single ribonucleotide at 3'- or 5'-end of nick DNA is distinctly affected depending on architecture of 3'-terminus:template base pairing. Finally, our LIG1 structures demonstrated the importance of DNA end alignment governed by the distance to nick site through F635 and F872 residues, and single-molecule measurements showed similar nick DNA binding modes for LIG1 wild-type and active site mutants in real-time. Overall, our study provides a mechanistic insight into the mechanism by which conserved F635 and F872 residues contribute to ligation efficiency of nick repair intermediates that mimic DNA polymerase-mediated mismatch, damaged, or ribonucleotide insertion products and how LIG1 ensures faithful end joining at the final step of DNA repair to maintain genome integrity.

Profound synthetic lethality between SMARCAL1 and FANCM

DNA replication stress is a threat to genome integrity. The large SNF2-family of ATPases participates in preventing and mitigating DNA replication stress by employing their ATP-driven motor to remodel DNA or DNA-bound proteins. To understand the contribution of these ATPases in genome maintenance, we undertook CRISPR-based synthetic lethality screens in human cells with three SNF2-type ATPases: SMARCAL1, ZRANB3, and HLTF. Here, we show that SMARCAL1 displays a profound synthetic-lethal interaction with FANCM, another ATP-dependent translocase involved in DNA replication and genome stability. Their combined loss causes severe genome instability that we link to chromosome breakage at loci enriched in simple repeats, which are known to challenge replication fork progression. Our findings illuminate a critical genetic buffering mechanism that provides an essential function for maintaining genome integrity.

Longitudinal analysis of genetic and epigenetic changes in human pluripotent stem cells in the landscape of culture-induced abnormality

Human embryonic stem cells (hESCs) are naturally equipped to maintain genome integrity to minimize genetic mutations during early embryo development. However, genetic aberration risks and subsequent cellular changes in hESCs during in vitro culture pose a significant threat to stem cell therapy. While a few studies have reported specific somatic mutations and copy number variations (CNVs), the molecular mechanisms underlying the acquisition of ‘culture-adapted phenotypes’ by hESCs are largely unknown. Therefore, we conducted comprehensive genomic, single-cell transcriptomic, and single-cell ATAC-seq analyses of an isogenic hESC model displaying definitive ‘culture-adapted phenotypes’. We found that hESCs lacking TP53, in which loss-of-function mutations were identified in human pluripotent stem cells (hPSCs), presented a surge in somatic mutations. Notably, hPSCs with a copy number gain of 20q11.21 during early passage did not present ‘culture-adapted phenotypes’ or BCL2L1 induction. Single-cell RNA-seq and ATAC-seq analyses revealed active transcriptional regulation at the 20q11.21 locus. Furthermore, the induction of BCL2L1 and TPX2 to trigger ‘culture-adapted phenotypes’ was associated with epigenetic changes facilitating TEA domain (TEAD) binding. These results suggest that 20q11.21 copy number gain and additional epigenetic changes are necessary for expressing ‘culture-adapted phenotypes’ by activating gene transcription at this specific locus.

New Insights into the Fanconi Anemia Pathogenesis: A Crosstalk Between Inflammation and Oxidative Stress.

Fanconi anemia (FA) represents a rare hereditary disease; it develops due to germline pathogenic variants in any of the 22 currently discovered FANC genes, which interact with the Fanconi anemia/breast cancer-associated (FANC/BRCA) pathway to maintain genome integrity. FA is characterized by a triad of clinical traits, including congenital anomalies, bone marrow failure (BMF) and multiple cancer susceptibility. Due to the complex genetic background and a broad spectrum of FA clinical symptoms, the diagnostic process is complex and requires the use of classical cytogenetic, molecular cytogenetics and strictly molecular methods. Recent findings indicate the interplay of inflammation, oxidative stress, disrupted mitochondrial metabolism, and impaired intracellular signaling in the FA pathogenesis. Additionally, a shift in the balance towards overproduction of proinflammatory cytokines and prooxidant components in FA is associated with advanced myelosuppression and ultimately BMF. Although the mechanism of BMF is very complex and needs further clarification, it appears that mutual interaction between proinflammatory cytokines and redox imbalance causes pancytopenia. In this review, we summarize the available literature regarding the clinical phenotype, genetic background, and diagnostic procedures of FA. We also highlight the current understanding of disrupted autophagy process, proinflammatory state, impaired signaling pathways and oxidative genotoxic stress in FA pathogenesis.

Mutagenic ligation of polβ mismatch insertion products during 8-oxoG bypass by LIG1 and LIG3α at the downstream steps of base excision repair pathway.

Base excision repair (BER) maintains genome integrity by fixing oxidized bases that could be formed when reactive oxygen species attack directly on the DNA. We previously reported the importance of a proper coordination at the downstream steps involving gap filling by DNA polymerase (pol) β and subsequent nick sealing by DNA ligase (LIG) 1 or 3α. Yet, how the fidelity of 8-oxoG bypass by polβ affects the efficiency of ligation remains unclear. Here, we show that LIG1 can seal nick products of polβ after both dATP and dCTP insertions during 8- oxoG bypass, while ribonucleotide insertions completely diminish the repair coordination with both ligases, highlighting a critical role for nucleotide selectivity in maintaining BER accuracy. Furthermore, our results demonstrate that LIG3α exhibits an inability to ligate nicks of polβ dCTP:8-oxoG insertion or with preinserted 3'-dC:8-oxoG. Finally, AP-Endonuclease 1 (APE1) proofreads nick repair intermediates containing 3'-dA/rA and 3'-dC/rC mismatches templating 8-oxoG. Overall, our findings provide a mechanistic insight into how the dual coding potential of the oxidative lesion and identity of BER ligase govern mutagenic versus error-free repair outcomes at the final steps and how the ribonucleotide challenge compromises the BER coordination leading to the formation of deleterious repair intermediates.

O6-Alkylguanine-DNA Alkyltransferase Maintains Genome Integrity by Forming DNA-Protein Cross-Links during Inflammation-Associated Peroxynitrite-Mediated DNA Damage.

Inflammation is an early immune response against invading pathogens and damaged tissue. Although beneficial, uncontrolled inflammation leads to various diseases including cancer in a chronic setting. Peroxynitrite (PN) is a major reactive nitrogen species generated during inflammation. It produces various DNA lesions including 8-nitro-guanine which spontaneously converts into abasic sites, resulting in DNA strand breakage, and is suspected to be mutagenic. Here, we report the discovery of a previously unrecognized function of the human repair protein O6-alkylguanine-DNA alkyltransferase (hAGT or MGMT). We showed that hAGT through its active site nucleophilic Cys145 thiolate spontaneously reacts with 8-nitro-guanine in DNA to form a stable DNA-protein cross-link (DPC). Interestingly, the process of DPC formation provided protection from PN-mediated genome instability, growth arrest, and apoptosis. The Cys145 mutant of hAGT failed to form a DPC and was unable to protect cells from inflammation-associated PN-mediated cytotoxicity. Gel-shift, dot blot, and UV-vis assays showed formation of a covalent linkage between PN-damaged DNA and hAGT through its active site Cys145. Finally, expression of hAGT was found to be significantly increased by induced macrophages and PN. The data presented here clearly demonstrated hAGT as a dual-function protein that along with DNA repair is capable of maintaining genomic integrity and providing protection from the toxicity caused by PN-mediated DNA damage. Although DPCs are known to be detrimental to the cell, recently, multiple pathways have been identified in normal cells for their repair.

Unraveling the Role of JMJD1B in Genome Stability and the Malignancy of Melanomas.

Genome instability relies on preserving the chromatin structure, with any histone imbalances threating DNA integrity. Histone synthesis occurs in the cytoplasm, followed by a maturation process before their nuclear translocation. This maturation involves protein folding and the establishment of post-translational modifications. Disruptions in this pathway hinder chromatin assembly and contribute to genome instability. JMJD1B, a histone demethylase, not only regulates gene expression but also ensures a proper supply of histones H3 and H4 for the chromatin assembly. Reduced JMJD1B levels lead to the cytoplasmic accumulation of histones, causing defects in the chromatin assembly and resulting in DNA damage. To investigate the role of JMJD1B in regulating genome stability and the malignancy of melanoma tumors, we used a JMJD1B/KDM3B knockout in B16F10 mouse melanoma cells to perform tumorigenic and genome instability assays. Additionally, we analyzed the transcriptomic data of human cutaneous melanoma tumors. Our results show the enhanced tumorigenic properties of JMJD1B knockout melanoma cells both in vitro and in vivo. The γH2AX staining, Micrococcal Nuclease sensitivity, and comet assays demonstrated increased DNA damage and genome instability. The JMJD1B expression in human melanoma tumors correlates with a lower mutational burden and fewer oncogenic driver mutations. Our findings highlight JMJD1B's role in maintaining genome integrity by ensuring a proper histone supply to the nucleus, expanding its function beyond gene expression regulation. JMJD1B emerges as a crucial player in preserving genome stability and the development of melanoma, with a potential role as a safeguard against oncogenic mutations.

The histone demethylase JMJ27 acts during the UV-induced modulation of H3K9me2 landscape and facilitates photodamage repair.

Plants have evolved sophisticated DNA repair mechanisms to cope with the deleterious effects of ultraviolet (UV)-induced DNA damage. Indeed, DNA repair pathways cooperate with epigenetic-related processes to efficiently maintain genome integrity. However, it remains to be deciphered how photodamages are recognized within different chromatin landscapes, especially in compacted genomic regions such as constitutive heterochromatin. Here we combined cytogenetics and epigenomics to identify that UV-C irradiation induces modulation of the main epigenetic mark found in constitutive heterochromatin, H3K9me2. We demonstrated that the histone demethylase, Jumonji27 (JMJ27), contributes to the UV-induced reduction of H3K9me2 content at chromocentres. In addition, we identified that JMJ27 forms a complex with the photodamage recognition factor, DNA Damage Binding protein 2 (DDB2), and that the fine-tuning of H3K9me2 contents orchestrates DDB2 dynamics on chromatin in response to UV-C exposure. Hence, this study uncovers the unexpected existence of an interplay between photodamage repair and H3K9me2 homeostasis.

NEAT1 modulates the TIRR/53BP1 complex to maintain genome integrity.

Tudor Interacting Repair Regulator (TIRR) is an RNA-binding protein (RBP) that interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. We utilized iCLIP to identify RNAs that directly bind to TIRR within cells, identifying the long non-coding RNA NEAT1 as the primary RNA partner. The high affinity of TIRR for NEAT1 is due to prevalent G-rich motifs in the short isoform (NEAT1_1) region of NEAT1. This interaction destabilizes the TIRR/53BP1 complex, promoting 53BP1's function. NEAT1_1 is enriched during the G1 phase of the cell cycle, thereby ensuring that TIRR-dependent inhibition of 53BP1's function is cell cycle-dependent. TDP-43, an RBP that is implicated in neurodegenerative diseases, modulates the TIRR/53BP1 complex by promoting the production of the NEAT1 short isoform, NEAT1_1. Together, we infer that NEAT1_1, and factors regulating NEAT1_1, may impact 53BP1-dependent DNA repair processes, with implications for a spectrum of diseases.

The role of RAD51 regulators and variants in primary ovarian insufficiency, endometriosis,and polycystic ovary syndrome.

The study of RAD51 regulators in female reproductive diseases has novel biomarker potential and implications for therapeutic advancement. Regulators of RAD51 play important roles in maintaining genome integrity and variations in these genes have been identified in female reproductive diseases including primary ovarian insufficiency (POI), endometriosis, and polycystic ovary syndrome (PCOS). RAD51 modulators change RAD51 activity in homologous recombination, replication stress, and template switching pathways. However, molecular implications of these proteins in primary ovarian insufficiency, endometriosis, and polycystic ovary syndrome have been understudied. For each reproductive disease, we provide its definition, current diagnostic and therapeutic treatment strategies, and associated genetic variations. Variants were discovered in RAD51, and regulators including DMC1, RAD51B, SWS1, SPIDR, XRCC2and BRCA2 linked with POI. Endometriosis is associated with variants in XRCC3, BRCA1and CSB genes. Variants in BRCA1 were associated with PCOS.Our analysis identifiednovel biomarkers for POI (DMC1 and RAD51B) and PCOS (BRCA1). Further biochemical and cellular analyses of RAD51 regulator functions in reproductive disorders will advance our understanding of the pathogenesis of these diseases.