TY - JOUR
T1 - DNA polymerase (POLQ) is important for repair of DNA double-strand breaks caused by fork collapse
AU - Wang, Zi
AU - Song, Yadong
AU - Li, Shibo
AU - Kurian, Sunil
AU - Xiang, Rong
AU - Chiba, Takuya
AU - Wu, Xiaohua
N1 - Funding Information:
This work is supported by California Breast Cancer Research Program (CBCRP) Grant 23IB and National Institutes of Health Grants CA187052, CA197995, and GM080677 (to X. W.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the respon-sibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2019 Wang et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2019/3/15
Y1 - 2019/3/15
N2 - DNA polymerase (POLQ) plays an important role in alternative nonhomologous end joining or microhomology-Mediated end joining (alt-NHEJ/MMEJ). Here, we show that POLQ is not only required for MMEJ to repair DNA double-strand breaks (DSBs) generated by endonucleases such as I-SceI or Cas9, but is also needed for repair of DSBs derived from DNA nicks generated by Cas9 nickase. Consistently, we found that POLQ deficiency leads to sensitivity to topoisomerase inhibitors that cause DNA single-strand break (SSB) accumulation at replication forks and to ATR inhibitors that induce replication fork collapse. These studies support the function of POLQ in coping with replication stress and repairing DSBs upon fork collapse. POLQ overexpression is present in many cancer types and is associated with poor prognosis, including breast cancer regardless of BRCA1 status. We provide proof-of-concept evidence to support a novel cancer treatment strategy that combines POLQ inhibition with administration of topoisomerase or ATR inhibitors, which induces replication stress and fork collapse. Given the prevalence of POLQ overexpression in tumors, such strategy may have a significant impact on developing targeted cancer treatment.
AB - DNA polymerase (POLQ) plays an important role in alternative nonhomologous end joining or microhomology-Mediated end joining (alt-NHEJ/MMEJ). Here, we show that POLQ is not only required for MMEJ to repair DNA double-strand breaks (DSBs) generated by endonucleases such as I-SceI or Cas9, but is also needed for repair of DSBs derived from DNA nicks generated by Cas9 nickase. Consistently, we found that POLQ deficiency leads to sensitivity to topoisomerase inhibitors that cause DNA single-strand break (SSB) accumulation at replication forks and to ATR inhibitors that induce replication fork collapse. These studies support the function of POLQ in coping with replication stress and repairing DSBs upon fork collapse. POLQ overexpression is present in many cancer types and is associated with poor prognosis, including breast cancer regardless of BRCA1 status. We provide proof-of-concept evidence to support a novel cancer treatment strategy that combines POLQ inhibition with administration of topoisomerase or ATR inhibitors, which induces replication stress and fork collapse. Given the prevalence of POLQ overexpression in tumors, such strategy may have a significant impact on developing targeted cancer treatment.
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U2 - 10.1074/jbc.RA118.005188
DO - 10.1074/jbc.RA118.005188
M3 - Article
C2 - 30655289
AN - SCOPUS:85062984033
SN - 0021-9258
VL - 294
SP - 3909
EP - 3919
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 11
ER -