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

Elodie Hatchi (), Liana Goehring, Serena Landini, Konstantina Skourti-Stathaki, Derrick K. DeConti, Fieda O. Abderazzaq, Priyankana Banerjee, Timothy M. Demers, Yaoyu E. Wang, John Quackenbush and David M. Livingston ()
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Elodie Hatchi: Harvard Medical School
Liana Goehring: Harvard Medical School
Serena Landini: Harvard Medical School
Konstantina Skourti-Stathaki: Wellcome Centre for Cell Biology, University of Edinburgh
Derrick K. DeConti: Harvard T. H. Chan School of Public Health
Fieda O. Abderazzaq: Harvard Medical School
Priyankana Banerjee: Harvard Medical School
Timothy M. Demers: Harvard Medical School
Yaoyu E. Wang: Harvard T. H. Chan School of Public Health
John Quackenbush: Harvard T. H. Chan School of Public Health
David M. Livingston: Harvard Medical School

Nature, 2021, vol. 591, issue 7851, 665-670

Abstract: Abstract Strong connections exist between R-loops (three-stranded structures harbouring an RNA:DNA hybrid and a displaced single-strand DNA), genome instability and human disease1–5. 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 heterochromation6. Pause sites are also protected against endogenous single-stranded DNA breaks by BRCA17. 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 integrity8. 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.

Date: 2021
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DOI: 10.1038/s41586-020-03150-2

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