BRCA2-HSF2BP oligomeric ring disassembly by BRME1 promotes homologous recombination.

Science advances 2023 Oct 27

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In meiotic homologous recombination (HR), BRCA2 facilitates loading of the recombinases RAD51 and DMC1 at the sites of double-strand breaks (DSBs). The HSF2BP-BRME1 complex interacts with BRCA2. Its absence causes a severe reduction in recombinase loading at meiotic DSB. We previously showed that, in somatic cancer cells ectopically producing HSF2BP, DNA damage can trigger HSF2BP-dependent degradation of BRCA2, which prevents HR. Here, we report that, upon binding to BRCA2, HSF2BP forms octameric rings that are able to interlock into a large ring-shaped 24-mer. Addition of BRME1 leads to dissociation of both of these ring structures and cancels the disruptive effect of HSF2BP on cancer cell resistance to DNA damage. It also prevents BRCA2 degradation during interstrand DNA crosslink repair in Xenopus egg extracts. We propose that, during meiosis, the control of HSF2BPBRCA2 oligomerization by BRME1 ensures timely assembly of the ring complex that concentrates BRCA2 and controls its turnover, thus promoting HR.

Citation

Rania Ghouil, Simona Miron, Koichi Sato, Dejan Ristic, Sari E van Rossum-Fikkert, Pierre Legrand, Malika Ouldali, Jean-Marie Winter, Virginie Ropars, Gabriel David, Ana-Andreea Arteni, Claire Wyman, Puck Knipscheer, Roland Kanaar, Alex N Zelensky, Sophie Zinn-Justin. BRCA2-HSF2BP oligomeric ring disassembly by BRME1 promotes homologous recombination. Science advances. 2023 Oct 27;9(43):eadi7352