HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair

Koichi Sato, Inger Brandsma, Sari E van Rossum-Fikkert, Nicole Verkaik, Anneke B Oostra, Josephine C Dorsman, Dik C van Gent, Puck Knipscheer, Roland Kanaar, Alex N Zelensky

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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 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.

Original languageEnglish
Pages (from-to)2442-2456
Number of pages15
JournalNucleic Acids Research
Volume48
Issue number5
DOIs
Publication statusPublished - 18 Mar 2020

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    Sato, K., Brandsma, I., van Rossum-Fikkert, S. E., Verkaik, N., Oostra, A. B., Dorsman, J. C., van Gent, D. C., Knipscheer, P., Kanaar, R., & Zelensky, A. N. (2020). HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair. Nucleic Acids Research, 48(5), 2442-2456. https://doi.org/10.1093/nar/gkz1219