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

• Published in: Nature (London) Vol. 591; no. 7851; pp. 665 - 670
• Main Authors: Hatchi, Elodie, Goehring, Liana, Landini, Serena, Skourti-Stathaki, Konstantina, DeConti, Derrick K., Abderazzaq, Fieda O., Banerjee, Priyankana, Demers, Timothy M., Wang, Yaoyu E., Quackenbush, John, Livingston, David M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.03.2021; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/89; 38/15; 38/71; 38/77; 38/88; 38/90; 38/91; 45/22; 631/208/211; 631/337/1427; 631/45/500; 631/67/1347; 692/308; Antisense RNA; Argonaute Proteins - metabolism; BRCA mutations; BRCA1 protein; BRCA1 Protein - metabolism; Breast cancer; Cell Cycle Proteins - metabolism; Deoxyribonucleic acid; DNA; DNA Damage; DNA Repair; Eukaryotic Initiation Factors - metabolism; Fanconi Anemia Complementation Group N Protein - metabolism; Gene expression; Genomes; Genomic instability; HeLa Cells; Homeostasis; Humanities and Social Sciences; Humans; Methods; MicroRNA; MicroRNAs; multidisciplinary; Physiological aspects; Physiology; R-loops; Rad52 DNA Repair and Recombination Protein - metabolism; Rad52 protein; Repair; Resting Phase, Cell Cycle; Ribonuclease III - metabolism; Ribonucleic acid; RNA; RNA Interference; RNA polymerase; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; RNA-mediated interference; Science; Science (multidisciplinary); Single-stranded DNA; Stem cells; Transcription termination; Tumor suppressor genes; Tumors; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-020-03150-2

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. Single-stranded, DNA-damage-associated small RNAs generated by a BRCA1–RNA-interference complex promote PALB2–RAD52-mediated DNA repair at transcriptional termination pause sites that contain R-loops and are rich in single-stranded DNA breaks in both quiescent and proliferating cells.