Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness |
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| Authors: | Vijayalakshmi Kari Simon J Baumgart Andreas Mund Marian Grade Hüseyin Sirma Ronald Simon Hans Will Matthias Dobbelstein Ekkehard Dikomey Steven A Johnsen |
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| Affiliation: | 1. Department of General, Visceral and Pediatric Surgery, University Medical Center G?ttingen, G?ttingen, GermanyThese authors contributed equally to this work;2. Department of General, Visceral and Pediatric Surgery, University Medical Center G?ttingen, G?ttingen, Germany;3. Chromatin Structure and Function Group, Protein Signaling Program, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;4. Institute of Pathology, University Medical Center Hamburg‐Eppendorf, Hamburg, Germany;5. Institute for Tumor Biology, University Medical Center Hamburg‐Eppendorf, Hamburg, Germany;6. Institute of Molecular Oncology, University Medical Center G?ttingen, G?ttingen, Germany |
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| 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. |
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| Keywords: | CHD1 chromatin DNA repair PARP inhibitor prostate cancer |
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