The proper repair of deleterious DNA lesions such as double strand breaks prevents genomic instability and carcinogenesis. In yeast, the Rad52 protein mediates DSB repair via homologous recombination. In mammalian cells, despite the presence of the RAD52 protein, the tumour suppressor protein BRCA2 acts as the predominant mediator during homologous recombination. For decades, it has been believed that the RAD52 protein played only a back-up role in the repair of DSBs performing an error-prone single strand annealing (SSA). Recent studies have identified several new functions of the RAD52 protein and have drawn attention to its important role in genome maintenance. Here, we show that RAD52 activities are enhanced by interacting with a small and highly acidic protein called DSS1. Binding of DSS1 to RAD52 changes the RAD52 oligomeric conformation, modulates its DNA binding properties, stimulates SSA activity and promotes strand invasion. Our work introduces for the first time RAD52 as another interacting partner of DSS1 and shows that both proteins are important players in the SSA and BIR pathways of DSB repair.

• MeSH
• DNA opravný a rekombinační protein Rad52 genetika   MeSH
• DNA vazebné proteiny genetika   MeSH
• dvouřetězcové zlomy DNA MeSH
• genom lidský genetika   MeSH
• homologní rekombinace genetika   MeSH
• karcinogeneze genetika   MeSH
• lidé MeSH
• nestabilita genomu genetika   MeSH
• oprava DNA genetika   MeSH
• osteosarkom genetika   patologie   MeSH
• proteasomový endopeptidasový komplex genetika   MeSH
• protein BRCA2 genetika   MeSH
• Saccharomyces cerevisiae - proteiny genetika   MeSH
• Saccharomyces cerevisiae genetika   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Aging may be characterized as the progressive increase of the risk of death caused by a decrease of almost all bodily functions. While a great number of model organism studies have established the role of DNA double strand breaks (DSBs) as one of the main causes of aging, few studies have examined whether common polymorphisms in human DSB repair genes influence aging and mortality. More importantly, to the best of our knowledge, no longitudinal study has thus far examined the link between polymorphisms in DSB repair and the risk of death. This longitudinal study thus analyses whether four common polymorphisms (rs2155209, rs7963551, rs17105278, rs2735383) in four selected DSB repair genes (MRE11A, RAD52, RAD51B, NBS1) influence the hazard of age-adjusted death in a cohort of patients with typical symptoms of ischemic heart disease. The results have shown that rs7963551 G/T heterozygotes exhibit a significantly increased hazard of death when compared with the combined GG and TT homozygotes (HR=1.42, 95% CI: 1.06-1.91, p=0.018). This study indicates that the SNP affecting efficiency of DSB repair may influence aging in humans.

• MeSH
• DNA opravný a rekombinační protein Rad52 genetika   fyziologie   MeSH
• DNA vazebné proteiny genetika   MeSH
• dvouřetězcové zlomy DNA MeSH
• genetická predispozice k nemoci MeSH
• genotyp MeSH
• heterozygot MeSH
• jednonukleotidový polymorfismus * MeSH
• kardiovaskulární nemoci genetika   mortalita   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• multivariační analýza MeSH
• mutace MeSH
• oprava DNA MeSH
• poškození DNA MeSH
• proporcionální rizikové modely MeSH
• riziko MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Genetic variations in 3' untranslated regions of target genes may affect microRNA binding, resulting in differential protein expression. microRNAs regulate DNA repair, and single-nucleotide polymorphisms in miRNA binding sites (miRSNPs) may account for interindividual differences in the DNA repair capacity. Our hypothesis is that miRSNPs in relevant DNA repair genes may ultimately affect cancer susceptibility and impact prognosis.In the present study, we analysed the association of polymorphisms in predicted microRNA target sites of double-strand breaks (DSBs) repair genes with colorectal cancer (CRC) risk and clinical outcome. Twenty-one miRSNPs in non-homologous end-joining and homologous recombination pathways were assessed in 1111 cases and 1469 controls. The variant CC genotype of rs2155209 in MRE11A was strongly associated with decreased cancer risk when compared with the other genotypes (OR 0.54, 95% CI 0.38-0.76, p = 0.0004). A reduced expression of the reporter gene was observed for the C allele of this polymorphism by in vitro assay, suggesting a more efficient interaction with potentially binding miRNAs. In colon cancer patients, the rs2155209 CC genotype was associated with shorter survival while the TT genotype of RAD52 rs11226 with longer survival when both compared with their respective more frequent genotypes (HR 1.63, 95% CI 1.06-2.51, p = 0.03 HR 0.60, 95% CI 0.41-0.89, p = 0.01, respectively).miRSNPs in DSB repair genes involved in the maintenance of genomic stability may have a role on CRC susceptibility and clinical outcome.

• MeSH
• 3' nepřekládaná oblast genetika   MeSH
• DNA opravný a rekombinační protein Rad52 genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• genotyp MeSH
• homologní protein MRE11 genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• míra přežití MeSH
• mladý dospělý MeSH
• nádorové biomarkery genetika   MeSH
• následné studie MeSH
• oprava DNA genetika   MeSH
• prognóza MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• vazebná místa MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10(-4)). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10(-3)) and LUSC (p = 9x10(-4)) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10(-48) and p = 3x10(-29) in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.

• MeSH
• demografie MeSH
• DNA opravný a rekombinační protein Rad52 genetika   MeSH
• fyzikální mapování chromozomů MeSH
• genetická predispozice k nemoci * MeSH
• genetické lokusy * MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 12 genetika   MeSH
• lokus kvantitativního znaku genetika   MeSH
• nádory hlavy a krku genetika   MeSH
• nádory plic genetika   MeSH
• počítačová simulace MeSH
• rizikové faktory MeSH
• spinocelulární karcinom genetika   MeSH
• studie případů a kontrol MeSH
• zárodečné buňky MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH

The replication protein A (RPA) is involved in most, if not all, nuclear metabolism involving single-stranded DNA. Here, we show that RPA is involved in genome maintenance at stalled replication forks by the homologous recombination repair system in humans. Depletion of the RPA protein inhibited the formation of RAD51 nuclear foci after hydroxyurea-induced replication stalling leading to persistent unrepaired DNA double-strand breaks (DSBs). We demonstrate a direct role of RPA in homology directed recombination repair. We find that RPA is dispensable for checkpoint kinase 1 (Chk1) activation and that RPA directly binds RAD52 upon replication stress, suggesting a direct role in recombination repair. In addition we show that inhibition of Chk1 with UCN-01 decreases dissociation of RPA from the chromatin and inhibits association of RAD51 and RAD52 with DNA. Altogether, our data suggest a direct role of RPA in homologous recombination in assembly of the RAD51 and RAD52 proteins. Furthermore, our data suggest that replacement of RPA with the RAD51 and RAD52 proteins is affected by checkpoint signalling.

• MeSH
• aktivace enzymů MeSH
• CDC geny MeSH
• DNA opravný a rekombinační protein Rad52 genetika   metabolismus   MeSH
• hydroxymočovina metabolismus   MeSH
• inhibitory syntézy nukleových kyselin metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• oprava DNA * MeSH
• poškození DNA MeSH
• proteinkinasy genetika   metabolismus   MeSH
• rekombinasa Rad51 metabolismus   MeSH
• replikace DNA * MeSH
• replikační protein A genetika   metabolismus   MeSH
• signální transdukce * fyziologie   MeSH
• Check Tag
• lidé MeSH