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DNA polymerase θ (POLQ) is important for repair of DNA double-strand breaks caused by fork collapse
| Content Provider | Scilit |
|---|---|
| Author | Wang, Zi Song, Yadong Li, Shibo Kurian, Sunil Xiang, Rong Chiba, Takuya Wu, Xiaohua |
| Copyright Year | 2019 |
| Description | Journal: Journal of Biological Chemistry DNA polymerase theta (POLQ) plays an important role in alternative non-homologous end joining or micro-homology-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 revealed a new 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. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422074/pdf http://www.jbc.org/content/early/2019/01/17/jbc.RA118.005188.full.pdf |
| Ending Page | 3919 |
| Page Count | 11 |
| Starting Page | 3909 |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| DOI | 10.1074/jbc.ra118.005188 |
| Journal | Journal of Biological Chemistry |
| Issue Number | 11 |
| Volume Number | 294 |
| Language | English |
| Publisher | Elsevier BV |
| Publisher Date | 2019-03-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Journal of Biological Chemistry Biochemistry and Molecular Biology Atr Kinase Dna Double-strand Break Repair Dna Repair Dna Replication Stress Breast Cancer Genome Integrity Genomic Instability Microhomology-mediated End Joining |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
