DNA polymerase (POLQ) is important for repair of DNA double-strand breaks caused by fork collapse

Zi Wang, Yadong Song, Shibo Li, Sunil Kurian, Rong Xiang, Takuya Chiba, Xiaohua Wu

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3909-3919
Number of pages11
JournalJournal of Biological Chemistry
Volume294
Issue number11
DOIs
Publication statusPublished - 2019 Jan 1

Fingerprint

Oncology
Double-Stranded DNA Breaks
DNA-Directed DNA Polymerase
Joining
Repair
Topoisomerase Inhibitors
Single-Stranded DNA Breaks
Endonucleases
Deoxyribonuclease I
DNA
Tumors
Neoplasms
DNA End-Joining Repair
Breast Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

DNA polymerase (POLQ) is important for repair of DNA double-strand breaks caused by fork collapse. / Wang, Zi; Song, Yadong; Li, Shibo; Kurian, Sunil; Xiang, Rong; Chiba, Takuya; Wu, Xiaohua.

In: Journal of Biological Chemistry, Vol. 294, No. 11, 01.01.2019, p. 3909-3919.

Research output: Contribution to journalArticle

Wang, Zi ; Song, Yadong ; Li, Shibo ; Kurian, Sunil ; Xiang, Rong ; Chiba, Takuya ; Wu, Xiaohua. / DNA polymerase (POLQ) is important for repair of DNA double-strand breaks caused by fork collapse. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 11. pp. 3909-3919.
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abstract = "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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AU - Chiba, Takuya

AU - Wu, Xiaohua

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