Huntingtin (HTT) interactome in regulation of DNA repair/remodeling and RNA processing pathways
Tamara Ratovitski, Chloe D Holland, Robert N O’Meally, Alexey V Shevelkin, Siddhi V Kamath, Tianze Shi, Matthew J Rodriguez, Robert N Cole, Mali Jiang, Christopher A Ross
TL;DR
The study explores how the huntingtin protein interacts with other proteins to regulate DNA repair and RNA processing, which may contribute to Huntington's disease.
Contribution
The study identifies new interactions of huntingtin with DNA repair and RNA processing proteins, suggesting a novel role in integrating these pathways.
Findings
HD neurons show impaired DNA double-strand break repair response.
HTT interacts with DNA-PKcs and nuclear speckle proteins TCERG1 and MED15.
HTT may act as a scaffolding intermediary in DNA repair and RNA processing.
Abstract
This study of protein interactions of HTT using multiple approaches supports its role in facilitating the emerging integration and interplay between DNA damage/remodeling and RNA processing pathways. Huntington’s disease (HD), an uncurable neurodegenerative disorder, is caused by CAG repeat expansion in the HD gene encoding mutant huntingtin protein. DNA damage response is implicated in HD pathogenesis. We used multiple approaches to assess normal and mutant HTT interactomes in the context of genotoxic stress. We show that double-strand break (DSB) repair response is impaired in HD neurons, which are more vulnerable to DSB-induced stress. We found that S1181 phosphorylation of HTT is regulated by DSB, and can be carried out by DNA-PK. Functional interaction of HTT with a major DSB kinase DNA-PKcs and association of both proteins with nuclear speckles suggest a role of HTT in DSB repair…
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Taxonomy
TopicsGenetic Neurodegenerative Diseases · Amyotrophic Lateral Sclerosis Research · RNA Research and Splicing