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

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 hyper-mutable nature of dMMR, it is unknown how dMMR activates the cGAS-STING pathway. We show here that loss of the MutLa subunit MLH1, whose defect is responsible for similar to 50% of dMMR cancers, results in loss of MutLa-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.

Automated summary

This study revealed that loss of MutLa subunit MLH1 leads to production of neoantigens and activation of the cGAS-STING pathway, affecting DNA repair process and ultimately causing chromosomal abnormalities and DNA release. This unknown MMR mechanism has significant implications for genome stability and cancer therapy.