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

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin ( HTT ) gene. The repeat-expanded HTT encodes a mutated HTT (mHTT), which is known to induce DNA double-strand breaks (DSBs), activation of the cGAS–STING pathway, and apoptosis in HD. However, the mechanism by which mHTT triggers these events is unknown. Here, we show that HTT interacts with both exonuclease 1 (Exo1) and MutLα (MLH1–PMS2), a negative regulator of Exo1. While the HTT–Exo1 interaction suppresses the Exo1-catalyzed DNA end resection during DSB repair, the HTT–MutLα interaction functions to stabilize MLH1. However, mHTT displays a significantly reduced interaction with Exo1 or MutLα, thereby losing the ability to regulate Exo1. Thus, cells expressing mHTT exhibit rapid MLH1 degradation and hyperactive DNA excision, which causes severe DNA damage and cytosolic DNA accumulation. This activates the cGAS–STING pathway to mediate apoptosis. Therefore, we have identified unique functions for both HTT and mHTT in modulating DNA repair and the cGAS–STING pathway-mediated apoptosis by interacting with MLH1. Our work elucidates the mechanism by which mHTT causes HD.