MLH1 Deficiency-Triggered DNA Hyperexcision by Exonuclease 1 Activates the cGAS-STING Pathway

Junhong Guan, Changzheng Lu, Qihuang Jin, Huiming 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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)109-121.e5
JournalCancer Cell
Volume39
Issue number1
DOIs
StatePublished - Jan 11 2021

Keywords

  • DNA breaks
  • MLH1
  • RPA exhaustion
  • Rad51
  • cGAS-STING
  • chromosome instability
  • cytosolic DNA
  • exonuclease 1
  • mismatch repair

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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