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

• Published in: EMBO reports Vol. 17; no. 11; pp. 1609 - 1623
• Main Authors: Kari, Vijayalakshmi, Mansour, Wael Yassin, Raul, Sanjay Kumar, Baumgart, Simon J, Mund, Andreas, Grade, Marian, Sirma, Hüseyin, Simon, Ronald, Will, Hans, Dobbelstein, Matthias, Dikomey, Ekkehard, Johnsen, Steven A
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 01.11.2016; Nature Publishing Group UK; John Wiley and Sons Inc
• Subjects: Biomarkers; Cancer therapies; Carrier Proteins - genetics; Cell Line, Tumor; CHD1; Chromatin; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA Helicases - deficiency; DNA Helicases - genetics; DNA Helicases - metabolism; DNA polymerase; DNA Repair; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; EMBO03; EMBO13; Endodeoxyribonucleases; Genes; Humans; Inhibitors; Male; Nuclear Proteins - genetics; Ovarian cancer; PARP inhibitor; Poly(ADP-ribose) Polymerase Inhibitors - metabolism; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Recombinational DNA Repair; prostate cancer; chromatin; CHD1; DNA repair; PARP inhibitor
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201642352

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. Synopsis Chromo‐domain helicase DNA‐binding protein‐1 (CHD1) promotes HR‐mediated DSB repair. The depletion of CHD1 enhances cellular sensitivity to PARP inhibitors, which has potential therapeutic implications for CHD1‐depleted prostate cancers. CHD1 is required for the recruitment of CtIP and efficient DNA DSB repair. CHD1 facilitates the opening of chromatin at DSB and promotes HR repair. CHD1 depletion elicits cellular sensitivity to PARP inhibition. Graphical Abstract Chromo‐domain helicase DNA‐binding protein‐1 (CHD1) promotes HR‐mediated DSB repair. The depletion of CHD1 enhances cellular sensitivity to PARP inhibitors, which has potential therapeutic implications for CHD1‐depleted prostate cancers.