Regulation of HTT-mediated DNA damage repair and chromatin remodeling complexes

Persistent accumulation of DNA double-strand breaks (DSBs) in neuronal DNA is one of the early pathologicalfeatu res of Huntington’s disease (HD), a terminal neurodegenerative disease, suggesting that DSB repair is compromised in HD. We have discovered that huntingtin forms a specialized DNA repair complex, and that this novel complex maintains neuronal genome integrity and function. The proposed research will test whether there is a link between disruption of the activity of this complex and compromised neuronal genome integrity and neuronal gene expression in the presence of the mutant Huntingtin protein, which could inform strategies to target early processes to slow the progression of the disease.