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

Autor:	Sun X; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390.; The Ministry of Education Key Laboratory of Reproductive Genetics, Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China., Liu L; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390., Wu C; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390., Li X; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390., Guo J; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390., Zhang J; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390., Guan J; Cui-ying Experimental Center, Lanzhou University Second Hospital, Lanzhou 730030, China., Wang N; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human behavior, University of California, Los Angeles, CA 90095.; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095., Gu L; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390., Yang XW; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human behavior, University of California, Los Angeles, CA 90095.; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095., Li GM; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390.; Institute for Cancer Research, Chinese Institutes for Medical Research, Beijing 100069, China.; School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Mar 26; Vol. 121 (13), pp. e2313652121. Date of Electronic Publication: 2024 Mar 18.
DOI:	10.1073/pnas.2313652121
Abstrakt:	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. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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