BRCA1 and RNAi factors promote repair mediated by small RNAs and PALB2-RAD52

Article

关键词: DNA-DAMAGE RESPONSE;    HOMOLOGOUS RECOMBINATION;    CELL-CYCLE;    R-LOOPS;    GENOME INTEGRITY;    DIRECTED REPAIR;    NONCODING RNAS;    RECRUITMENT;    RAD52;    INSTABILITY;   

DOI  :  10.1038/s41586-020-03150-2

来源: SCIE

【 摘 要 】

Strong connections exist between R-loops (three-stranded structures harbouring an RNA:DNA hybrid and a displaced single-strand DNA), genome instability and human disease(1-5). Indeed, R-loops are favoured in relevant genomic regions as regulators of certain physiological processes through which homeostasis is typically maintained. For example, transcription termination pause sites regulated by R-loops can induce the synthesis of antisense transcripts that enable the formation of local, RNA interference (RNAi)-driven heterochromation(6). Pause sites are also protected against endogenous single-stranded DNA breaks by BRCA1(7). Hypotheses about how DNA repair is enacted at pause sites include a role for RNA, which is emerging as a normal, albeit unexplained, regulator of genome integrity(8). Here we report that a species of single-stranded, DNA-damage-associated small RNA (sdRNA) is generated by a BRCA1-RNAi protein complex. sdRNAs promote DNA repair driven by the PALB2-RAD52 complex at transcriptional termination pause sites that form R-loops and are rich in single-stranded DNA breaks. sdRNA repair operates in both quiescent (G0) and proliferating cells. Thus, sdRNA repair can occur in intact tissue and/or stem cells, and may contribute to tumour suppression mediated by BRCA1.

【 授权许可】

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