TY - JOUR
T1 - HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair
AU - Sato, Koichi
AU - Brandsma, Inger
AU - van Rossum-Fikkert, Sari E.
AU - Verkaik, Nicole
AU - Oostra, Anneke B.
AU - Dorsman, Josephine C.
AU - van Gent, Dik C.
AU - Knipscheer, Puck
AU - Kanaar, Roland
AU - Zelensky, Alex N.
PY - 2020/3/18
Y1 - 2020/3/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85081075752&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/nar/gkz1219
DO - https://doi.org/10.1093/nar/gkz1219
M3 - Article
C2 - 31960047
SN - 0305-1048
VL - 48
SP - 2442
EP - 2456
JO - Nucleic acids research
JF - Nucleic acids research
IS - 5
ER -