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Mutant huntingtin protein induces MLH1 degradation, DNA hyperexcision, and cGAS-STING-dependent apoptosis

Xiao Sun1,2, Lu Liu1, Chao Wu1

  • 1Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390.

Proceedings of the National Academy of Sciences of the United States of America
|March 18, 2024
PubMed

Insights

Mutated huntingtin protein in Huntington's disease disrupts DNA repair by destabilizing MLH1, leading to DNA damage and apoptosis via the cGAS-STING pathway.

Area of Science:

  • Neurodegenerative diseases
  • Molecular biology
  • Genetics

Background:

  • Huntington's disease (HD) is an inherited neurodegenerative disorder linked to expanded CAG repeats in the huntingtin (HTT) gene.
  • Mutated HTT (mHTT) is known to cause DNA double-strand breaks (DSBs), cGAS-STING pathway activation, and apoptosis, but the underlying mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism by which mHTT induces DNA damage and apoptosis in Huntington's disease.
  • To identify the interactions of HTT and mHTT with DNA repair proteins and their role in regulating DNA repair and cell death.

Main Methods:

  • Investigated the interactions between HTT/mHTT and DNA repair proteins Exonuclease 1 (Exo1) and MutLα (MLH1-PMS2).
  • Assessed the impact of mHTT on Exo1 activity, MLH1 stability, DNA repair, and cGAS-STING pathway activation in cellular models.

Main Results:

  • Normal HTT interacts with Exo1 and MutLα, suppressing DNA end resection and stabilizing MLH1.
  • mHTT shows reduced interaction with Exo1 and MutLα, leading to MLH1 degradation and hyperactive DNA excision.
  • This results in severe DNA damage, cytosolic DNA accumulation, cGAS-STING pathway activation, and apoptosis.

Conclusions:

  • HTT and mHTT play distinct roles in modulating DNA repair and cGAS-STING pathway-mediated apoptosis through interactions with MLH1.
  • The study reveals a novel mechanism by which mHTT causes Huntington's disease pathology via dysregulated DNA repair and immune pathway activation.

Keywords:
Exo1Huntington’s diseaseMutLαcGAS-STINGmHTT

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