BRCA2-HSF2BP oligomeric ring disassembly by BRME1 promotes homologous recombination

• Published in: Science advances 2023-10, Vol.9 (43), p.eadi7352-eadi7352
• Main Authors: Ghouil, Rania, Miron, Simona, Sato, Koichi, Ristic, Dejan, van Rossum-Fikkert, Sari E, Legrand, Pierre, Ouldali, Malika, Winter, Jean-Marie, Ropars, Virginie, David, Gabriel, Arteni, Ana-Andreea, Wyman, Claire, Knipscheer, Puck, Kanaar, Roland, Zelensky, Alex N, Zinn-Justin, Sophie
• Format: Article
• Language: English
• Subjects: Biochemistry, Molecular Biology; Biomedicine and Life Sciences; Cancer; DNA Damage; DNA Repair; DNA-Binding Proteins - metabolism; Health and Medicine; Homologous Recombination; Life Sciences; Rad51 Recombinase - genetics; Rad51 Recombinase - metabolism; SciAdv r-articles; Structural Biology
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adi7352

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 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.