# Huntingtin (HTT) interactome in regulation of DNA repair/remodeling and RNA processing pathways

## 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.

## Key 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 mechanism; however, physiological outcome of these interactions remains to be examined. We revealed HTT interactions with other proteins associated with nuclear speckles, TCERG1 and MED15, whose loci are genetic modifiers for HD, and with chromatin remodeling complex BAF. These interactions may position HTT as an important scaffolding intermediary providing integrated regulation of gene expression and RNA processing in the context of DNA repair mechanisms.