Deregulation of BRCA1 leads to impaired spatiotemporal dynamics of γ-H2AX and DNA damage responses in Huntington's disease.

Molecular Neurobiology
Gye Sun JeonHoon Ryu

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 recruitme...Continue Reading

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Citations

Sep 28, 2013·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Camille Brochier, Brett Langley
Jan 24, 2014·International Journal of Molecular Sciences·Serena BarralAdalberto Merighi
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Dec 22, 2019·Brain Sciences·Masanori KuriharaAtsushi Iwata
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Jun 27, 2021·Archives of Biochemistry and Biophysics·Mariarosaria D'ErricoEugenia Dogliotti
Jul 6, 2021·Brain Communications·Emily Leung, Lili-Naz Hazrati

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