HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair
Sato, Koichi; Brandsma, Inger; van Rossum-Fikkert, Sari E; Verkaik, Nicole; Oostra, Anneke B; Dorsman, Josephine C; van Gent, Dik C; Knipscheer, Puck; Kanaar, Roland; Zelensky, Alex N
(2020) Nucleic acids research, volume 48, issue 5, pp. 2442 - 2456
(Article)
Abstract
The tumor suppressor BRCA2 is essential for homologous recombination (HR), replication fork stability and DNA interstrand crosslink (ICL) repair in vertebrates. We show that ectopic production of HSF2BP, a BRCA2-interacting protein required for meiotic HR during mouse spermatogenesis, in non-germline human cells acutely sensitize them to ICL-inducing agents (mitomycin C
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and cisplatin) and PARP inhibitors, resulting in a phenotype characteristic of cells from Fanconi anemia (FA) patients. We biochemically recapitulate the suppression of ICL repair and establish that excess HSF2BP compromises HR by triggering the removal of BRCA2 from the ICL site and thereby preventing the loading of RAD51. This establishes ectopic expression of a wild-type meiotic protein in the absence of any other protein-coding mutations as a new mechanism that can lead to an FA-like cellular phenotype. Naturally occurring elevated production of HSF2BP in tumors may be a source of cancer-promoting genomic instability and also a targetable vulnerability.
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Keywords: Animals, BRCA2 Protein/metabolism, Carrier Proteins/metabolism, Cell Cycle Proteins/metabolism, Cell Line, DNA Damage, DNA Repair, Fanconi Anemia/genetics, Heat-Shock Proteins/metabolism, Homologous Recombination, Humans, Mice, Protein Binding, Proteolysis, Rad51 Recombinase/metabolism, Xenopus, Genetics, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 0305-1048
Publisher: Oxford University Press
Note: Funding Information: Uehara Memorial Foundation (to K.S.); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to K.S.); JSPS Postdoctoral Fellowship for Research Abroad (to K.S.); Netherlands Organization for Scientific Research (NWO) [VIDI 700.10.421 to P.K. and Gravitation Program CancerGenomiCs.nl]; Dutch Cancer Society [KWF HUBR 2015-7736, EMCR 2008-4045, Ride for the Roses Cancer Research Grant]; European Community’s Seventh Framework Program [FP7/2007-2013, HEALTH-F2-2010-259893]. This research is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society. Funding for open access charge: Dutch Cancer Society. Conflict of interest statement. None declared. Publisher Copyright: © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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