| Literature DB >> 33338427 |
Junhong Guan1, Changzheng Lu2, Qihuang Jin1, Huiming Lu1, Xiang Chen3, Lei Tian4, Yanbin Zhang5, Janice Ortega1, Junqiu Zhang1, Silvia Siteni6, Mingyi Chen2, Liya Gu1, Jerry W Shay6, Anthony J Davis1, Zhijian J Chen3, Yang-Xin Fu7, Guo-Min Li8.
Abstract
Tumors with defective mismatch repair (dMMR) are responsive to immunotherapy because of dMMR-induced neoantigens and activation of the cGAS-STING pathway. While neoantigens result from the hypermutable nature of dMMR, it is unknown how dMMR activates the cGAS-STING pathway. We show here that loss of the MutLα subunit MLH1, whose defect is responsible for ~50% of dMMR cancers, results in loss of MutLα-specific regulation of exonuclease 1 (Exo1) during DNA repair. This leads to unrestrained DNA excision by Exo1, which causes increased single-strand DNA formation, RPA exhaustion, DNA breaks, and aberrant DNA repair intermediates. Ultimately, this generates chromosomal abnormalities and the release of nuclear DNA into the cytoplasm, activating the cGAS-STING pathway. In this study, we discovered a hitherto unknown MMR mechanism that modulates genome stability and has implications for cancer therapy.Entities:
Keywords: DNA breaks; MLH1; RPA exhaustion; Rad51; cGAS-STING; chromosome instability; cytosolic DNA; exonuclease 1; mismatch repair
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Year: 2020 PMID： 33338427 PMCID： PMC8666006 DOI： 10.1016/j.ccell.2020.11.004
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743