Huntingtin interactome reveals huntingtin role in regulation of double strand break DNA damage response (DSB/DDR), chromatin remodeling and RNA processing pathways DOI Creative Commons
Tamara Ratovitski,

Chloe D. Holland,

Robert N. O’Meally

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 28, 2024

Abstract Huntington’s Disease (HD), a progressive neurodegenerative disorder with no disease-modifying therapies, is caused by CAG repeat expansion in the HD gene encoding polyglutamine-expanded huntingtin (HTT) protein. Mechanisms of cellular pathogenesis and functions normal mutant HTT proteins are still not completely understood. protein has numerous interaction partners, it likely provides scaffold for assembly multiprotein complexes many which may be altered HD. Previous studies have implicated DNA damage response pathogenesis. Gene transcription RNA processing also emerged as molecular mechanisms associated Here we used multiple approaches to identify interactors context stress. Our results indicate that interacts involved regulation interconnected repair/remodeling pathways. We present evidence role double strand break repair mechanism. demonstrate functional major kinase DNA-PKcs association both nuclear speckles. show S1181 phosphorylation regulated DSB, can carried out (at least vitro ) DNA-PK. Furthermore, interactions binding speckles, including two encoded genes at modifier loci, TCERG1 MED15, chromatin remodeling complex BAF. These position an important scaffolding intermediary providing integrated expression mechanisms.

Language: Английский

Huntingtin interactome reveals huntingtin role in regulation of double strand break DNA damage response (DSB/DDR), chromatin remodeling and RNA processing pathways DOI Creative Commons
Tamara Ratovitski,

Chloe D. Holland,

Robert N. O’Meally

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 28, 2024

Abstract Huntington’s Disease (HD), a progressive neurodegenerative disorder with no disease-modifying therapies, is caused by CAG repeat expansion in the HD gene encoding polyglutamine-expanded huntingtin (HTT) protein. Mechanisms of cellular pathogenesis and functions normal mutant HTT proteins are still not completely understood. protein has numerous interaction partners, it likely provides scaffold for assembly multiprotein complexes many which may be altered HD. Previous studies have implicated DNA damage response pathogenesis. Gene transcription RNA processing also emerged as molecular mechanisms associated Here we used multiple approaches to identify interactors context stress. Our results indicate that interacts involved regulation interconnected repair/remodeling pathways. We present evidence role double strand break repair mechanism. demonstrate functional major kinase DNA-PKcs association both nuclear speckles. show S1181 phosphorylation regulated DSB, can carried out (at least vitro ) DNA-PK. Furthermore, interactions binding speckles, including two encoded genes at modifier loci, TCERG1 MED15, chromatin remodeling complex BAF. These position an important scaffolding intermediary providing integrated expression mechanisms.

Language: Английский

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