小柯机器人

美国哈佛医学院David M. Livingston和Elodie Hatchi课题组合作取得最新进展。他们揭示BRCA1和RNAi因子促进小RNA和PALB2–RAD52介导的修复。相关论文发表在2021年2月3日出版的《自然》杂志上。

他们报告说，BRCA1-RNAi蛋白复合物可产生一种与DNA损伤相关的单链小RNA（sdRNA）。 sdRNA促进由PALB2-RAD52复合体驱动的DNA修复在转录终止暂停位点形成R环，并富含单链DNA断裂。sdRNA修复在静止（G0）和增殖细胞中均起作用。因此，sdRNA修复可以发生在完整的组织和/或干细胞中，并且可能有助于BRCA1介导的肿瘤抑制。

据悉，R环（具有RNA：DNA杂合体和置换的单链DNA的三链结构）、基因组不稳定性和人类疾病之间存在明显的联系。实际上，R-环在相关的基因组区域中是有利的，作为通常维持稳态的某些生理过程的调节剂。例如，受R环调控的转录终止暂停位点可诱导合成反义转录本，从而形成局部RNA干扰（RNAi）驱动的异染色质。暂停位点也可以通过BRCA17保护免受内源性单链DNA断裂的影响。

关于在暂停位点进行DNA修复的方式的假设包括RNA的功能，这种修复的出现是正常的，尽管无法解释，这也是基因组完整性的调节剂。

附：英文原文

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

Author: 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, David M. Livingston

Issue&Volume: 2021-02-03

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 disease1,2,3,4,5. 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.

DOI: 10.1038/s41586-020-03150-2

Source: https://www.nature.com/articles/s41586-020-03150-2

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