Journal
EMBO JOURNAL
Volume 40, Issue 7, Pages -Publisher
WILEY
DOI: 10.15252/embj.2020106018
Keywords
BRCA2; DNA double‐ strand breaks; DNA‐ RNA hybrids; homologous recombination; R‐ loops
Categories
Funding
- Agence National de Recherche [ANR-17-CE12-0016]
- Institut National du Cancer [INCa-DGOS_8706]
- Ligue contre le Cancer
- French Breast Cancer Association: Ruban Rose
- European Research Council [ERC2014 AdG669898 TARLOOP]
- Spanish Ministry of Economy and Competitiveness [BFU2016-75058-P]
- Fundacion Vencer el Cancer
- European Union (FEDER)
- Institut Curie
- CNRS
- Association pour la Recherche sur le Cancer (ARC)
- French Ministry of Education
- Asociacion Espanola Contra el Cancer (AECC)
- Juan de la Cierva-Incorporation grant
- Spanish Ministry of Economy, Industry, and Competitiveness
- Fondation de France
- [ANR-10-INBS-04]
- Agence Nationale de la Recherche (ANR) [ANR-17-CE12-0016] Funding Source: Agence Nationale de la Recherche (ANR)
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BRCA2-deficient cells accumulate DNA-RNA hybrids, and the BRCA2-DDX5 interaction helps in unwinding these structures, enhancing helicase activity and promoting repair of double-strand breaks.
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.
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