BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment

Giuseppina D’Alessandro (), Donna Rose Whelan, Sean Michael Howard, Valerio Vitelli, Xavier Renaudin, Marek Adamowicz, Fabio Iannelli, Corey Winston Jones-Weinert, MiYoung Lee, Valentina Matti, Wei Ting C. Lee, Michael John Morten, Ashok Raraakrishnan Venkitaraman, Petr Cejka, Eli Rothenberg and Fabrizio d’Adda di Fagagna ()
Additional contact information
Giuseppina D’Alessandro: IFOM, the FIRC Institute of Molecular Oncology
Donna Rose Whelan: NYU School of Medicine
Sean Michael Howard: Università della Svizzera italiana
Valerio Vitelli: IFOM, the FIRC Institute of Molecular Oncology
Xavier Renaudin: University of Cambridge
Marek Adamowicz: IFOM, the FIRC Institute of Molecular Oncology
Fabio Iannelli: IFOM, the FIRC Institute of Molecular Oncology
Corey Winston Jones-Weinert: IFOM, the FIRC Institute of Molecular Oncology
MiYoung Lee: University of Cambridge
Valentina Matti: IFOM, the FIRC Institute of Molecular Oncology
Wei Ting C. Lee: NYU School of Medicine
Michael John Morten: NYU School of Medicine
Ashok Raraakrishnan Venkitaraman: University of Cambridge
Petr Cejka: Università della Svizzera italiana
Eli Rothenberg: NYU School of Medicine
Fabrizio d’Adda di Fagagna: IFOM, the FIRC Institute of Molecular Oncology

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract DNA double-strand breaks (DSBs) are toxic DNA lesions, which, if not properly repaired, may lead to genomic instability, cell death and senescence. Damage-induced long non-coding RNAs (dilncRNAs) are transcribed from broken DNA ends and contribute to DNA damage response (DDR) signaling. Here we show that dilncRNAs play a role in DSB repair by homologous recombination (HR) by contributing to the recruitment of the HR proteins BRCA1, BRCA2, and RAD51, without affecting DNA-end resection. In S/G2-phase cells, dilncRNAs pair to the resected DNA ends and form DNA:RNA hybrids, which are recognized by BRCA1. We also show that BRCA2 directly interacts with RNase H2, mediates its localization to DSBs in the S/G2 cell-cycle phase, and controls DNA:RNA hybrid levels at DSBs. These results demonstrate that regulated DNA:RNA hybrid levels at DSBs contribute to HR-mediated repair.

Date: 2018
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DOI: 10.1038/s41467-018-07799-2

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