MLH1
DNA错配修复
DNA修复
DNA
生物
癌症研究
刺
细胞生物学
核酸外切酶
分子生物学
遗传学
DNA聚合酶
工程类
航空航天工程
作者
Junhong Guan,Changzheng Lu,Qihuang Jin,Haijun Lu,Xiang Chen,Lei Tian,Yanbin Zhang,Janice Ortega,Junqiu Zhang,Silvia Siteni,Mingyi Chen,Liya Gu,Jerry W. Shay,Anthony J. Davis,Zhijian J. Chen,Yang Xin Fu,Guo Min Li
出处
期刊:Cancer Cell
[Elsevier]
日期:2021-01-01
卷期号:39 (1): 109-121.e5
被引量:102
标识
DOI:10.1016/j.ccell.2020.11.004
摘要
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.
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