Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness

Vijayalakshmi Kari, Wael Yassin Mansour, Sanjay Kumar Raul, Simon J. Baumgart, Andreas Mund, Marian Grade, Hüseyin Sirma, Ronald Simon, Hans Will, Matthias Dobbelstein, Ekkehard Dikomey, Steven A. Johnsen

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

The CHD1 gene, encoding the chromo-domain helicase DNA-binding protein-1, is one of the most frequently deleted genes in prostate cancer. Here, we examined the role of CHD1 in DNA double-strand break (DSB) repair in prostate cancer cells. We show that CHD1 is required for the recruitment of CtIP to chromatin and subsequent end resection during DNA DSB repair. Our data support a role for CHD1 in opening the chromatin around the DSB to facilitate the recruitment of homologous recombination (HR) proteins. Consequently, depletion of CHD1 specifically affects HR-mediated DNA repair but not non-homologous end joining. Together, we provide evidence for a previously unknown role of CHD1 in DNA DSB repair via HR and show that CHD1 depletion sensitizes cells to PARP inhibitors, which has potential therapeutic relevance. Our findings suggest that CHD1 deletion, like BRCA1/2 mutation in ovarian cancer, may serve as a marker for prostate cancer patient stratification and the utilization of targeted therapies such as PARP inhibitors, which specifically target tumors with HR defects.

Original languageEnglish (US)
Pages (from-to)1609-1623
Number of pages15
JournalEMBO Reports
Volume17
Issue number11
DOIs
StatePublished - Nov 1 2016

Keywords

  • CHD1
  • DNA repair
  • PARP inhibitor
  • chromatin
  • prostate cancer

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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    Kari, V., Mansour, W. Y., Raul, S. K., Baumgart, S. J., Mund, A., Grade, M., Sirma, H., Simon, R., Will, H., Dobbelstein, M., Dikomey, E., & Johnsen, S. A. (2016). Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness. EMBO Reports, 17(11), 1609-1623. https://doi.org/10.15252/embr.201642352