title: Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex.
abstract: Huntington's disease (HD) is an age-dependent neurodegenerative disease. DNA repair pathways have recently been implicated as the most predominant modifiers of age of onset in HD patients. We report that endogenous huntingtin protein directly participates in oxidative DNA damage repair. Using novel chromobodies to detect endogenous human huntingtin in live cells, we show that localization of huntingtin to DNA damage sites is dependent on the kinase activity of ataxia telangiectasia mutated (ATM) protein. Super-resolution microscopy and biochemical assays revealed that huntingtin co-localizes with and scaffolds proteins of the DNA damage response pathway in response to oxidative stress. In HD patient fibroblasts bearing typical clinical HD allele lengths, we demonstrate that there is deficient oxidative DNA damage repair. We propose that DNA damage in HD is caused by dysfunction of the mutant huntingtin protein in DNA repair, and accumulation of DNA oxidative lesions due to elevated reactive oxygen species may contribute to the onset of HD.
authors.affiliation: Department of Biochemistry and Biomedical Research, McMaster University, HSC 4N54, 1200 Main Street West, Hamilton, Canada L8N3Z5.
authors.forename: Tamara
authors.initials: T
authors.lastname: Maiuri
authors.affiliation: Department of Biochemistry and Biomedical Research, McMaster University, HSC 4N54, 1200 Main Street West, Hamilton, Canada L8N3Z5.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mocle
authors.affiliation: Department of Biochemistry and Biomedical Research, McMaster University, HSC 4N54, 1200 Main Street West, Hamilton, Canada L8N3Z5.
authors.forename: Claudia L
authors.initials: CL
authors.lastname: Hung
authors.affiliation: Department of Biochemistry and Biomedical Research, McMaster University, HSC 4N54, 1200 Main Street West, Hamilton, Canada L8N3Z5.
authors.forename: Jianrun
authors.initials: J
authors.lastname: Xia
authors.affiliation: Center for Human and Clinical Genetics, Leiden University Medical Center, Postzone S4-0P, P.O. Box 9600 2300RC Leiden, The Netherlands.
authors.forename: Willeke M C
authors.initials: WM
authors.lastname: van Roon-Mom
authors.affiliation: Department of Biochemistry and Biomedical Research, McMaster University, HSC 4N54, 1200 Main Street West, Hamilton, Canada L8N3Z5.
authors.forename: Ray
authors.initials: R
authors.lastname: Truant
mesh_terms: D000483:Alleles; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018384:Oxidative Stress / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000071058:Huntingtin Protein; D017382:Reactive Oxygen Species; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins