Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness.
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.
Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany vkari1@gwdg.de steven.johnsen@med.uni-goettingen.de.
Vijayalakshmi
V
Kari
Department of Tumor Biology, National Cancer Institute, Cairo University, Cairo, Egypt.|Laboratory of Radiobiology and Experimental Radiooncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Wael Yassin
WY
Mansour
Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
Sanjay Kumar
SK
Raul
Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
Simon J
SJ
Baumgart
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.
Andreas
A
Mund
Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
Marian
M
Grade
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Hüseyin
H
Sirma
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Ronald
R
Simon
Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Hans
H
Will
Institute of Molecular Oncology, University Medical Center Göttingen, Göttingen, Germany.
Matthias
M
Dobbelstein
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Ekkehard
E
Dikomey
Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany vkari1@gwdg.de steven.johnsen@med.uni-goettingen.de.
Steven A
0000-0003-1198-5805
SA
Johnsen
D015415:Biomarkers; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004706:Endodeoxyribonucleases; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D059767:Recombinational DNA Repair
D015415:Biomarkers; D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human; D004265:DNA Helicases; C080359:CHD1 protein, human
CHD1; DNA repair; PARP inhibitor; chromatin; prostate cancer