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

Area of Science:

• Molecular Biology
• Cancer Biology
• Immunology

Background:

• Defective mismatch repair (dMMR) tumors are sensitive to immunotherapy due to neoantigens and cGAS-STING pathway activation.
• The mechanism by which dMMR activates the cGAS-STING pathway remains unclear.

Purpose of the Study:

• To elucidate the molecular mechanism linking dMMR to cGAS-STING pathway activation.
• To identify the role of MLH1 in this process and its impact on DNA repair.

Main Methods:

• Investigated the function of MLH1, a subunit of MutLα, in DNA repair in dMMR cancer models.
• Analyzed the consequences of MLH1 loss on exonuclease 1 (Exo1) activity and DNA integrity.
• Assessed the generation of cytoplasmic DNA and subsequent cGAS-STING pathway activation.

Main Results:

• Loss of MLH1 disrupts MutLα-mediated regulation of Exo1 during DNA repair.
• Unrestrained Exo1 activity leads to increased single-strand DNA, RPA exhaustion, DNA breaks, and aberrant repair intermediates.
• These events result in chromosomal abnormalities and cytoplasmic release of nuclear DNA, activating the cGAS-STING pathway.

Conclusions:

• Discovered a novel mechanism where MLH1 loss in dMMR cancers triggers cGAS-STING activation via Exo1-mediated DNA damage.
• This pathway modulation has significant implications for developing targeted cancer therapies for dMMR tumors.