BRCA2-HSF2BP oligomeric ring disassembly by BRME1 promotes homologous recombination
Open accessPublished version of a preprint
Abstract
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-nucleotide oligomer. 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 HSF2BP-BRCA2 oligomerization by BRME1 ensures timely assembly of the ring complex that concentrates BRCA2 and controls its turnover, thus promoting HR.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
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- Authors
- Ghouil, R., Miron, S., Sato, K., Ristic, D., van Rossum-Fikkert, S. E., Legrand, P., Ouldali, M., Winter, J.-M., Ropars, V., David, G., Arteni, A.-A., Wyman, C., Knipscheer, P., Kanaar, R., Zelensky, A. N., & Zinn-Justin, S.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- University Medical Center Utrecht (NL)
- Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3000 CA, Rotterdam, Netherlands.
- Synchrotron SOLEIL (FR)
- Institut Pasteur (FR)
- Erasmus MC (NL)
- Leiden University Medical Center (NL)
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, France.
- Corresponding author
- Kanaar, Roland
- Zelensky, Alex N.
- ORCID
- Venue
- Science Advances
- Published
- 2023-10-27
- Volume
- 9
- Issue
- 43
- Pages
- eadi7352-eadi7352
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC10610910
- OpenAlex
- W4387969735
- Cited by
- 2
- References
- 1
- Citations by year
- 2024: 2
- FWCI
- 0.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- HAL (submittedVersion, cc-by-nc)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion, other-oa)
- Funders
- Japanese Biochemical Society
- Equipex
- Agence Nationale de la Recherche (ANR‐11‐EQPX‐008, ANR- 10-INSB-05, ANR-10, ANR-10-INBS-0005, ANR-11-EQPX-0008)
- European Synchrotron Radiation Facility
- Institut National de la Santé et de la Recherche Médicale
- KWF Kankerbestrijding
- Kanae Foundation for the Promotion of Medical Science
- French Infrastructure for Integrated Structural Biology (ANR-10- INSB-05, INSB-05)
- Oncode Institute
- Horizon 2020 Framework Programme (871037)
- H2020 European Research Council (101003210)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- BRCA2, homologous recombination, meiosis, RAD51, DMC1, DNA double-strand break repair, protein oligomerization, protein degradation, interstrand crosslink repair, DNA damage resistance, cancer cells
- MeSH terms
- DNA Damage, DNA Repair, DNA-Binding Proteins, Rad51 Recombinase, Homologous Recombination
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