Search results for: Rad52 Protein (Human)
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p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways.Classically, p53 tumor suppressor acts in transcription, apoptosis, and cell cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we find that p53 null and gain-of-function (GOF) mutations exhibit defects in restart of stalled or damaged DNA replication forks that drive genomic instability, which isgenetically separable from transcription activation. By assaying protein-DNA fork interactions in single cells, we unveil a p53-MLL3-enabled recruitment of MRE11 DNA replication restart nuclease. Importantly, p53 defects or depletion unexpectedly allow mutagenic RAD52 and POLθ pathways to hijack stalled forks, which we find reflected in p53 defective breast-cancer patient COSMIC mutational signatures. These data uncover p53 as a keystone regulator of replication homeostasis within a DNA restart network. Mechanistically, this has important implications for development of resistance in cancer therapy. Combined, these results define an unexpected role for p53-mediated suppression of replication genome instability.
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The global role for Cdc13 and Yku70 in preventing telomere resection across the genome.Yeast Cdc13 protein (related to human CTC1) maintains telomere stability by preventing 5'-3' end resection. While Cdc13 and Yku70/Yku80 proteins appear to prevent excessive resection, their combined contribution to maintenance of telomere ends across the genome and their relative roles at specific ends of different chromosomes have not been addressable because Cdc13 and Yku70/Yku80 double mutants are sickly. Using our PFGE-shift approach where large resected molecules have slower pulse field gel electrophoresis mobilities, along with methods for maintaining viable double mutants, we address end-resection on most chromosomes as well as telomere end differences. In this global approach to looking at ends of most chromosomes, we identify chromosomes with 1-end resections and end-preferences. We also identify chromosomes with resection at both ends, previously not possible. 10-20% of chromosomes exhibit PFGE-shift when cdc13-1 cells are switched to restrictive temperature (37 °C). In yku70Δ cdc13-1 mutants, there is a telomere resection "storm" with approximately half the chromosomes experiencing at least 1-end resection, ∼10 kb/telomere, due to exonuclease1 and many exhibiting 2-end resection. Unlike for random internal chromosome breaks, resection of telomere ends is not coordinated. Telomere restitution at permissive temperature is rapid (<1 h) in yku70Δ cdc13-1 cells. Surprisingly, survival can be high although strain background dependent. Given large amount of resected telomeres, we examined associated proteins. Up to 90% of cells have ≥1 Rfa1 (RPA) focus and 60% have multiple foci when ∼30-40 telomeres/cell are resected. The ends are dispersed in the nucleus suggesting wide distribution of resected telomeres across nuclear space. The previously reported Rad52 nuclear centers of repair for random DSBs also appear in cells with many resected telomere ends, suggesting a Rad52 commonality to the organization of single strand ends and/or limitation on interactions of single-strand ends with Rad52.
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RAD52 gene polymorphisms are associated with risk of colorectal cancer in a Chinese Han population.Upward trends in the incidence and mortality rates of colorectal cancer (CRC) in China over the past decade mean that it is critical to improve survival outcomes for patients with this malignancy. Analysis of genetic variants may identify biomarkers that have a role in CRC susceptibility and clinical outcomes in Chinese patients with CRC. RAD52 is a key mediator during DNA strand exchange and homologous recombination within mammalian cells. In this study, we explored the effects of RAD52 single nucleotide polymorphisms (SNPs) in the susceptibility and clinicopathological characteristics of Chinese Han patients with CRC. Five RAD52 SNPs (rs1051669, rs10774474, rs11571378, rs6489769, and rs7963551) were analyzed using TaqMan SNP genotyping in 281 patients with CRC and 309 healthy controls. Among those aged over 60 years in the total population, carriers of the variant C allele or at least one T allele of the rs1051669 SNP were at a lower risk of CRC than carriers of the wild-type CC variant of rs1051669, while in those carrying the rs7963551 SNP, the GT or GT+GG alleles were associated with an increased risk of CRC compared with patients carrying TT alleles. We indicated a significant correlation between RAD52 rs7963551 polymorphism and lymph node metastasis in CRC patients. In all patients, the T-T-T-T-T, C-T-T-T-T, and C-T-A-C-T haplotypes were associated with an increasing risk of CRC. Our findings suggest that 4 RAD52 SNPs (rs1051669, rs10774474, rs11571378, and rs6489769) might contribute to the prediction of CRC susceptibility. In conclusion, our study demonstrated that RAD52 polymorphisms were associated with CRC in a Chinese Han cohort.
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Replication fork reversal triggers fork degradation in BRCA2-defective cells.Besides its role in homologous recombination, the tumor suppressor BRCA2 protects stalled replication forks from nucleolytic degradation. Defective fork stability contributes to chemotherapeutic sensitivity of BRCA2-defective tumors by yet-elusive mechanisms. Using DNA fiber spreading and direct visualization of replication intermediates, we report that reversed replication forks are entry points for fork degradation in BRCA2-defective cells. Besides MRE11 and PTIP, we show that RAD52 promotes stalled fork degradation and chromosomal breakage in BRCA2-defective cells. Inactivation of these factors restores reversed fork frequency and chromosome integrity in BRCA2-defective cells. Conversely, impairing fork reversal prevents fork degradation, but increases chromosomal breakage, uncoupling fork protection, and chromosome stability. We propose that BRCA2 is dispensable for RAD51-mediated fork reversal, but assembles stable RAD51 nucleofilaments on regressed arms, to protect them from degradation. Our data uncover the physiopathological relevance of fork reversal and illuminate a complex interplay of homologous recombination factors in fork remodeling and stability.BRCA2 is involved in both homologous recombination (HR) and the protection of stalled replication forks from degradation. Here the authors reveal how HR factors cooperate in fork remodeling, showing that BRCA2 supports RAD51 loading on the regressed arms of reversed replication forks to protect them from degradation.
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Spectrum of germline mutations in smokers and non-smokers in Brazilian non-small-cell lung cancer (NSCLC) patients.Lung cancer (LC) is a leading cause of cancer-related mortality. Although smoking is the major risk factor, ~15% of all cases occur in never-smokers, suggesting that genetic factors play a role in LC predisposition. Indeed, germline mutations in the TP53 gene predispose to multiple cancer types, including LC. To date, few studies compared the somatic and germline mutational profiles of LC cases by smoking status, and none was reported in Brazilians. Whole-exome sequencing (WES) was performed on two pools (seven smokers and six non-smokers) of tumor-derived DNA using the Illumina HiSeq2000 platform. Files from pools were analyzed separately using Ingenuity®Variant AnalysisTM and Mendel,MD. Validation of all candidate variants was performed by Sanger sequencing. Subsequently, validated mutations were analyzed in germline DNA from the same patients and in ethnically matched controls. In addition, a single recurring Brazilian TP53 germline mutation (R337H) was genotyped in 45 non-small-cell lung cancer patients.Four novel germline variants in the ATAD2, AURKA, PTPRD and THBS1 genes were identified exclusively in smoker patients, and four germline missense variants in PLCD1, RAD52, CP and CDC6 genes were identified solely in non-smokers. There were 4/45 (8.9%) germline carriers of the R337H TP53 mutation. In conclusion, the recurring Brazilian TP53 mutation should be genotyped in all non-small-cell lung cancer in Brazil, regardless of smoking status. Distinct pathogenic mutations and novel sequence variants are detected in Brazilian non-small-cell lung cancer patients, by smoking status. The contribution of these sequence variants to LC pathogenesis remains to be further explored.
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gene overexpression represents a therapeutic target in papillary thyroid carcinoma.RAD52 motif containing 1 () encodes the RAD52 protein involved in DNA double-strand break repair and recombination events. However, the importance ofin papillary thyroid carcinoma (PTC) is largely unknown. In the present study, we examined the role ofin thyroid cancer. Theexpression in PTC patients was examined using immunohistochemistry. The expression levels ofmRNA in thyroid cancer cells were measured by quantitative real-time PCR (qRT-PCR). Lentivirus-mediated small interfering RNAs (siRNAs) were used to knock down theexpression in the K1 and TPC1 cells. Then, changes in thetarget gene expression were determined by qRT-PCR and Western blot. Cell proliferation was examined by a high content screening assay. Cell cycle distribution and apoptosis were detected by flow cytometric analysis and MTT analysis. We showed that theexpression was higher in PTC tissue compared to pericarcinous tissue.mRNA was found to be expressed by qRT-PCR. Using a lentivirus-based RNA interference (RNAi) approach, theexpression was significantly inhibited. The inhibition ofexpression by RNAi significantly impaired cell proliferation, increased apoptosis and arrested cells in the G2/M phase. These data showed thatwas highly expressed in PTC tissue and thyroid cancer cell lines. Moreover,may play an important role in cell proliferation, cell cycle distribution and apoptosis of human PTC cells.
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Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy.To maintain stable genomes and to avoid cancer and aging, cells need to repair a multitude of deleterious DNA lesions, which arise constantly in every cell. Processes that support genome integrity in normal cells, however, allow cancer cells to develop resistance to radiation and DNA-damaging chemotherapeutics. Chemical inhibition of the key DNA repair proteins and pharmacologically induced synthetic lethality have become instrumental in both dissecting the complex DNA repair networks and as promising anticancer agents. The difficulty in capitalizing on synthetically lethal interactions in cancer cells is that many potential targets do not possess well-defined small-molecule binding determinates. In this review, we discuss several successful campaigns to identify and leverage small-molecule inhibitors of the DNA repair proteins, from PARP1, a paradigm case for clinically successful small-molecule inhibitors, to coveted new targets, such as RAD51 recombinase, RAD52 DNA repair protein, MRE11 nuclease, and WRN DNA helicase.
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Enhancing CRISPR/Cas9-mediated homology-directed repair in mammalian cells by expressing Saccharomyces cerevisiae Rad52.Precise genome editing with desired point mutations can be generated by CRISPR/Cas9-mediated homology-directed repair (HDR) and is of great significance for gene function study, gene therapy and animal breeding. However, HDR efficiency is inherently low and improvements are necessitated. Herein, we determined that the HDR efficiency could be enhanced by expressing Rad52, a gene that is involved in the homologous recombination process. Both the Rad52 co-expression and Rad52-Cas9 fusion strategies yielded approximately 3-fold increase in HDR during the surrogate reporter assays in human HEK293T cells, as well as in the genome editing assays. Moreover, the enhancement effects of the Rad52-Cas9 fusion on HDR mediated by different (plasmid, PCR and ssDNA) donor templates were confirmed. We found that the HDR efficiency could be significantly improved to about 40% by the combined usage of Rad52 and Scr7. In addition, we also applied the fusion strategy for modifying the IGF2 gene of porcine PK15 cells, which further demonstrated a 2.2-fold increase in HDR frequency. In conclusion, our data suggests that Rad52-Cas9 fusion is a good option for enhancing CRISPR/Cas9-mediated HDR, which may be of use in future studies involving precise genome editing.
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Lingering single-strand breaks trigger Rad51-independent homology-directed repair of collapsed replication forks in the polynucleotide kinase/phosphatase mutant of fission yeast.The DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) protects genome integrity by restoring ligatable 5'-phosphate and 3'-hydroxyl termini at single-strand breaks (SSBs). In humans, PNKP mutations underlie the neurological disease known as MCSZ, but these individuals are not predisposed for cancer, implying effective alternative repair pathways in dividing cells. Homology-directed repair (HDR) of collapsed replication forks was proposed to repair SSBs in PNKP-deficient cells, but the critical HDR protein Rad51 is not required in PNKP-null (pnk1Δ) cells of Schizosaccharomyces pombe. Here, we report that pnk1Δ cells have enhanced requirements for Rad3 (ATR/Mec1) and Chk1 checkpoint kinases, and the multi-BRCT domain protein Brc1 that binds phospho-histone H2A (γH2A) at damaged replication forks. The viability of pnk1Δ cells depends on Mre11 and Ctp1 (CtIP/Sae2) double-strand break (DSB) resection proteins, Rad52 DNA strand annealing protein, Mus81-Eme1 Holliday junction resolvase, and Rqh1 (BLM/WRN/Sgs1) DNA helicase. Coupled with increased sister chromatid recombination and Rad52 repair foci in pnk1Δ cells, these findings indicate that lingering SSBs in pnk1Δ cells trigger Rad51-independent homology-directed repair of collapsed replication forks. From these data, we propose models for HDR-mediated tolerance of persistent SSBs with 3' phosphate in pnk1Δ cells.
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Alternative Lengthening of Telomeres Mediated by Mitotic DNA Synthesis Engages Break-Induced Replication Processes.Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. By analyzing telomerase-positive cells and their human TERC knockout-derived ALT human cell lines, we show that ALT cells harbor more fragile telomeres representing telomere replication problems. ALT-associated replication defects trigger mitotic DNA synthesis (MiDAS) at telomeres in a RAD52-dependent, but RAD51-independent, manner. Telomeric MiDAS is a conservative DNA synthesis process, potentially mediated by break-induced replication, similar to type II ALT survivors inReplication stresses induced by ectopic oncogenic expression of cyclin E, G-quadruplexes, or R-loop formation facilitate the ALT pathway and lead to telomere clustering, a hallmark of ALT cancers. The TIMELESS/TIPIN complex suppresses telomere clustering and telomeric MiDAS, whereas the SMC5/6 complex promotes them. In summary, ALT cells exhibit more telomere replication defects that result in persistent DNA damage responses at telomeres, leading to the engagement of telomeric MiDAS (spontaneous mitotic telomere synthesis) that is triggered by DNA replication stress, a potential driver of genomic duplications in cancer.
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