HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair

Author:

Sato Koichi1,Brandsma Inger2,van Rossum-Fikkert Sari E2,Verkaik Nicole2,Oostra Anneke B3,Dorsman Josephine C3,van Gent Dik C2,Knipscheer Puck1,Kanaar Roland2,Zelensky Alex N2ORCID

Affiliation:

1. Oncode Institute, Hubrecht Institute–KNAW and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands

2. Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands

3. Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands

Abstract

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.

Funder

Uehara Memorial Foundation

Mochida Memorial Foundation for Medical and Pharmaceutical Research

JSPS Postdoctoral Fellowship for Research Abroad

Netherlands Organization for Scientific Research

Dutch Cancer Society

EC Seventh Framework Programm

Publisher

Oxford University Press (OUP)

Subject

Genetics

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