HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair.

Autor:	Sato K; Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands., Brandsma I; Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands., van Rossum-Fikkert SE; Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands., Verkaik N; Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands., Oostra AB; Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands., Dorsman JC; Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands., van Gent DC; Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands., Knipscheer P; Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands., Kanaar R; Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands., Zelensky AN; Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2020 Mar 18; Vol. 48 (5), pp. 2442-2456.
DOI:	10.1093/nar/gkz1219
Abstrakt:	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 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. (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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