@article{e15a4867909e4ccaa3c73aa602a9243f,
title = "MLH1 Deficiency-Triggered DNA Hyperexcision by Exonuclease 1 Activates the cGAS-STING Pathway",
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.",
keywords = "DNA breaks, MLH1, RPA exhaustion, Rad51, cGAS-STING, chromosome instability, cytosolic DNA, exonuclease 1, mismatch repair",
author = "Junhong Guan and Changzheng Lu and Qihuang Jin and Huiming Lu and Xiang Chen and Lei Tian and Yanbin Zhang and Janice Ortega and Junqiu Zhang and Silvia Siteni and Mingyi Chen and Liya Gu and Shay, {Jerry W.} and Davis, {Anthony J.} and Chen, {Zhijian J.} and Fu, {Yang Xin} and Li, {Guo Min}",
note = "Funding Information: We thank Tanya T. Paull and Ga{\"e}lle Legube for providing ER-AsiSI-U2OS cells, Zhongsheng You for providing pExo1 antibody, and Jonathan Feinberg and Damiana Chiavolini for editing the manuscript. This work was supported in part by grants from the Cancer Prevention & Research Institute of Texas (CPRIT), United States, RR160101 to G.-M.L. and RR150072 and RP180725 to Y.-X.F., and from the National Institutes of Health, United States, CA092584 , CA162804 , and GM047251 to A.J.D. G.-M.L. and Y.-X.F. are CPRIT scholars. G.-M.L. is the Reece A. Overcash, Jr. Distinguished Chair for Research on Colon Cancer. Y.-X.F. holds the Mary Nell and Ralph B. Rogers Professorship in Immunology. Z.J.C. is an investigator of the Howard Hughes Medical Institute. J.W.S. holds the Southland Financial Corporation Distinguished Chair in Geriatrics Research. Funding Information: We thank Tanya T. Paull and Ga?lle Legube for providing ER-AsiSI-U2OS cells, Zhongsheng You for providing pExo1 antibody, and Jonathan Feinberg and Damiana Chiavolini for editing the manuscript. This work was supported in part by grants from the Cancer Prevention & Research Institute of Texas (CPRIT), United States, RR160101 to G.-M.L. and RR150072 and RP180725 to Y.-X.F. and from the National Institutes of Health, United States, CA092584, CA162804, and GM047251 to A.J.D. G.-M.L. and Y.-X.F. are CPRIT scholars. G.-M.L. is the Reece A. Overcash, Jr. Distinguished Chair for Research on Colon Cancer. Y.-X.F. holds the Mary Nell and Ralph B. Rogers Professorship in Immunology. Z.J.C. is an investigator of the Howard Hughes Medical Institute. J.W.S. holds the Southland Financial Corporation Distinguished Chair in Geriatrics Research. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2021",
month = jan,
day = "11",
doi = "10.1016/j.ccell.2020.11.004",
language = "English (US)",
volume = "39",
pages = "109--121.e5",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "1",
}