BRCA2 promotes DNA‐RNA hybrid resolution by DDX5 helicase at DNA breaks to facilitate their repair‡
- 26 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 40 (7), e106018
- https://doi.org/10.15252/embj.2020106018
Abstract
The BRCA2 tumor suppressor is a DNA double‐strand break (DSB) repair factor essential for maintaining genome integrity. BRCA2‐deficient cells spontaneously accumulate DNA‐RNA hybrids, a known source of genome instability. However, the specific role of BRCA2 on these structures remains poorly understood. Here we identified the DEAD‐box RNA helicase DDX5 as a BRCA2‐interacting protein. DDX5 associates with DNA‐RNA hybrids that form in the vicinity of DSBs, and this association is enhanced by BRCA2. Notably, BRCA2 stimulates the DNA‐RNA hybrid‐unwinding activity of DDX5 helicase. An impaired BRCA2‐DDX5 interaction, as observed in cells expressing the breast cancer variant BRCA2‐T207A, reduces the association of DDX5 with DNA‐RNA hybrids, decreases the number of RPA foci, and alters the kinetics of appearance of RAD51 foci upon irradiation. Our findings are consistent with DNA‐RNA hybrids constituting an impediment for the repair of DSBs by homologous recombination and reveal BRCA2 and DDX5 as active players in their removal.Keywords
Funding Information
- Agence Nationale de la Recherche (ANR‐17‐CE12‐0016)
- Institut National Du Cancer (INCa‐DGOS_8706)
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer (M33523)
- H2020 European Research Council (ERC2014 AdG669898 TARLOOP)
- Ministerio de Economía, Industria y Competitividad, Gobierno de España (BFU2016‐75058‐P)
- Centre National de la Recherche Scientifique
- Institut Curie
- Fundación Científica Asociación Española Contra el Cáncer
- Fondation de France
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