"Genome Instability and Cancer Predisposition" Group
Institut Curie, Orsay, France
BRCA2 promotes DNA-RNA hybrid resolution at DNA breaks to facilitate homologous recombination
A wealth of evidence suggests that proteins involved in RNA metabolism such as RNA binding proteins (RBPs) and RNA helicases are directly implicated in the DNA damage response (DDR) through interaction with DNA repair proteins. Indeed, a number of interactions of RBPs and DDR proteins have been described and an increasing number of RBPs are recruited to the DNA damage sites (Dutertre et al., 2014).
BRCA2 is a tumor suppressor protein that plays an important role in the repair of DSBs, inter-strand crosslinks and abnormal replicative DNA lesions by homologous recombination (HR) as well as protecting stalled replication forks from degradation. Interestingly, BRCA2 deficient cells accumulate RNA-DNA hybrids or R-loops (Bhatia et al., 2014), a known source of DNA damage, providing evidence for its role in either R-loop prevention or processing.
A mass spectrometry analysis performed in our laboratory has revealed a large number of proteins involved in RNA metabolism as candidate partners of BRCA2. In particular, RNA helicases and splicing factors were among the most enriched. We have confirmed the interaction between BRCA2 and the DDX5 RNA helicase in vitro and in cells. Our results show that BRCA2 strongly stimulates the recently reported DDX5 unwinding activity (Mersaoui et al., 2019), both on R-loops and RNA-DNA hybrids. Strikingly, a BRCA2 missense variant identified in breast cancer patients accumulates DSB-associated R-loops, making these findings relevant to cancer. Finally, both DDX5 depletion or expression of the BRCA2 variant with a reduced ability to interact with DDX5 show an altered kinetics of recruitment of the recombination protein RAD51 to DNA damage foci.
We propose that BRCA2 and DDX5 contribute to the processing of DNA-RNA structures that accumulate at DNA double-strand breaks to facilitate HR.
- Proper chromosome alignment depends on BRCA2 phosphorylation by PLK1. Ehlén Å, Martin C, Miron S, Julien M, Theillet FX, Ropars V, Sessa G, Beaurepere R, Boucherit V, Duchambon P, El Marjou A, Zinn-Justin S, Carreira A. (2020) Nat Commun 11:1819
- BRCA2 hypomorphic missense variants confer moderate risks of breast cancer. Shimelis H et al. (2017) Cancer Res 77:2789-2799
- A second DNA binding site in human BRCA2 promotes homologous recombination. von Nicolai C, Ehlén Å, Martin C, Zhang X, Carreira A. (2016) Nat Commun 7:12813
- BRCA2 regulates DMC1-mediated recombination through the BRC repeats. Martinez JS, von Nicolai C, Kim T, Ehlén Å, Mazin AV, Kowalczykowski SC, Carreira A. (2016) Proc Natl Acad Sci USA 113:3515-20
Contact: Florence Larminat (Florence.Larminat@ipbs.fr)
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11:00 - 12:00
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