Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness
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Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness. / Kari, Vijayalakshmi; Mansour Khalfallah, 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.
in: EMBO REP, Jahrgang 17, Nr. 11, 11.2016, S. 1609-1623.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness
AU - Kari, Vijayalakshmi
AU - Mansour Khalfallah, Wael Yassin
AU - Raul, Sanjay Kumar
AU - Baumgart, Simon J
AU - Mund, Andreas
AU - Grade, Marian
AU - Sirma, Hüseyin
AU - Simon, Ronald
AU - Will, Hans
AU - Dobbelstein, Matthias
AU - Dikomey, Ekkehard
AU - Johnsen, Steven A
N1 - © 2016 The Authors.
PY - 2016/11
Y1 - 2016/11
N2 - 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.
AB - 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.
U2 - 10.15252/embr.201642352
DO - 10.15252/embr.201642352
M3 - SCORING: Journal article
C2 - 27596623
VL - 17
SP - 1609
EP - 1623
JO - EMBO REP
JF - EMBO REP
SN - 1469-221X
IS - 11
ER -