title: Deregulation of BRCA1 leads to impaired spatiotemporal dynamics of γ-H2AX and DNA damage responses in Huntington's disease.
abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder of mid-life onset characterized by involuntary movements and progressive cognitive decline caused by a CAG repeat expansion in exon 1 of the Huntingtin (Htt) gene. Neuronal DNA damage is one of the major features of neurodegeneration in HD, but it is not known how it arises or relates to the triplet repeat expansion mutation in the Htt gene. Herein, we found that imbalanced levels of non-phosphorylated and phosphorylated BRCA1 contribute to the DNA damage response in HD. Notably, nuclear foci of γ-H2AX, the molecular component that recruits various DNA damage repair factors to damage sites including BRCA1, were deregulated when DNA was damaged in HD cell lines. BRCA1 specifically interacted with γ-H2AX via the BRCT domain, and this association was reduced in HD. BRCA1 overexpression restored γ-H2AX level in the nucleus of HD cells, while BRCA1 knockdown reduced the spatiotemporal propagation of γ-H2AX foci to the nucleoplasm. The deregulation of BRCA1 correlated with an abnormal nuclear distribution of γ-H2AX in striatal neurons of HD transgenic (R6/2) mice and BRCA1(+/-) mice. Our data indicate that BRCA1 is required for the efficient focal recruitment of γ-H2AX to the sites of neuronal DNA damage. Taken together, our results show that BRCA1 directly modulates the spatiotemporal dynamics of γ-H2AX upon genotoxic stress and serves as a molecular maker for neuronal DNA damage response in HD.
authors.affiliation: WCU Neurocytomics Group, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors.forename: Gye Sun
authors.initials: GS
authors.lastname: Jeon
authors.forename: Ki Yoon
authors.initials: KY
authors.lastname: Kim
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Hwang
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Jung
authors.forename: Sungkwan
authors.initials: S
authors.lastname: An
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Ouchi
authors.forename: Toru
authors.initials: T
authors.lastname: Ouchi
authors.forename: Neil
authors.initials: N
authors.lastname: Kowall
authors.forename: Junghee
authors.initials: J
authors.lastname: Lee
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000378:metabolism*; D002166:Camptothecin / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D025521:Tumor Suppressor Proteins; C475961:gamma-H2AX protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D002166:Camptothecin