BRCA2-HSF2BP oligomeric ring disassembly by BRME1 promotes homologous recombination

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, i...

Full description

Saved in:
Bibliographic Details
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adi7352