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HSF2BP Negatively Regulates Homologous Recombination in DNA Interstrand Crosslink Repair in Human Cells by Direct Interaction With BRCA2

Inger Brandsma, Koichi Sato, Sari E. van Rossum-Fikkert, Marcel Reuter, Hanny Odijk, Nicole Verkaik, Nathalie van den Tempel, Anneke B. Oostra, Dick H. W. Dekkers, Karel Bezstarosti, Jeroen A. A. Demmers, Joyce Lebbink, Claire Wyman, Josephine C. Dorsman, Dik C. van Gent, View ORCID ProfilePuck Knipscheer, View ORCID ProfileRoland Kanaar, View ORCID ProfileAlex N. Zelensky
doi: https://doi.org/10.1101/438945
Inger Brandsma
1Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
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Koichi Sato
2Oncode Institute, Hubrecht Institute–KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
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Sari E. van Rossum-Fikkert
1Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
3Department of Radiation Oncology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
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Marcel Reuter
1Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
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Hanny Odijk
1Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
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Nicole Verkaik
1Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
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Nathalie van den Tempel
1Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
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Anneke B. Oostra
4Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
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Dick H. W. Dekkers
5Department of Proteomics, Erasmus University Medical Center, Rotterdam, The Netherlands
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Karel Bezstarosti
5Department of Proteomics, Erasmus University Medical Center, Rotterdam, The Netherlands
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Jeroen A. A. Demmers
5Department of Proteomics, Erasmus University Medical Center, Rotterdam, The Netherlands
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Joyce Lebbink
1Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
3Department of Radiation Oncology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
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Claire Wyman
1Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
3Department of Radiation Oncology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands
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Josephine C. Dorsman
4Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
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Dik C. van Gent
1Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
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Puck Knipscheer
2Oncode Institute, Hubrecht Institute–KNAW and University Medical Center Utrecht, Utrecht, The Netherlands
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  • ORCID record for Puck Knipscheer
  • For correspondence: a.zelensky@erasmsumc.nl r.kanaar@erasmusmc.nl p.knipscheer@hubrecht.eu
Roland Kanaar
1Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
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  • ORCID record for Roland Kanaar
  • For correspondence: a.zelensky@erasmsumc.nl r.kanaar@erasmusmc.nl p.knipscheer@hubrecht.eu
Alex N. Zelensky
1Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
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  • ORCID record for Alex N. Zelensky
  • For correspondence: a.zelensky@erasmsumc.nl r.kanaar@erasmusmc.nl p.knipscheer@hubrecht.eu
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Summary

The tumor suppressor BRCA2 is essential for homologous recombination, replication fork stability and DNA interstrand crosslink (ICL) repair in vertebrates. We show that a functionally uncharacterized protein, HSF2BP, is involved in a novel, direct and highly evolutionarily conserved interaction with BRCA2. Although HSF2BP was previously described as testis-specific, we find it is expressed in mouse ES cells, in human cancer cell lines, and in tumor samples. Elevated levels of HSF2BP sensitize human cells 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 specifically compromises homologous recombination by preventing BRCA2 and RAD51 loading at the ICL. As increased ectopic expression of HSF2BP occurs naturally, we suggest that it can be considered as a causative agent in FA and a source of cancer-promoting genomic instability.

Footnotes

  • ↵7 Lead contact.

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Posted October 16, 2018.
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HSF2BP Negatively Regulates Homologous Recombination in DNA Interstrand Crosslink Repair in Human Cells by Direct Interaction With BRCA2
Inger Brandsma, Koichi Sato, Sari E. van Rossum-Fikkert, Marcel Reuter, Hanny Odijk, Nicole Verkaik, Nathalie van den Tempel, Anneke B. Oostra, Dick H. W. Dekkers, Karel Bezstarosti, Jeroen A. A. Demmers, Joyce Lebbink, Claire Wyman, Josephine C. Dorsman, Dik C. van Gent, Puck Knipscheer, Roland Kanaar, Alex N. Zelensky
bioRxiv 438945; doi: https://doi.org/10.1101/438945
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HSF2BP Negatively Regulates Homologous Recombination in DNA Interstrand Crosslink Repair in Human Cells by Direct Interaction With BRCA2
Inger Brandsma, Koichi Sato, Sari E. van Rossum-Fikkert, Marcel Reuter, Hanny Odijk, Nicole Verkaik, Nathalie van den Tempel, Anneke B. Oostra, Dick H. W. Dekkers, Karel Bezstarosti, Jeroen A. A. Demmers, Joyce Lebbink, Claire Wyman, Josephine C. Dorsman, Dik C. van Gent, Puck Knipscheer, Roland Kanaar, Alex N. Zelensky
bioRxiv 438945; doi: https://doi.org/10.1101/438945

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