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Deregulation of BRCA1 Leads to Impaired Spatiotemporal Dynamics of γ-H2AX and DNA Damage Responses in Huntington’s Disease

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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.

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Acknowledgments

We thank Dr. Marcy MacDonald (Harvard Medical School) for STHdh Q7/7 and STHdh Q111/111 cells. This study was supported by WCU Neurocytomics Program Grant (800–20080848) (H.R.) and SRC Grant (2010-0029-403) (H.R.) from KOSEF, NIH NS 067283-01A1 (H.R.), and R01CA79892 (TO), R01CA90631 (TO), and Susan G. Komen Breast Cancer Research Award (TO).

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Authors and Affiliations

  1. WCU Neurocytomics Group, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799, South Korea

    Gye Sun Jeon, Ki Yoon Kim, Yu Jin Hwang, Min-Kyung Jung & Hoon Ryu

  2. Department of Microbial Engineering, Functional Genoproteome Research Center, Konkuk University, Seoul, South Korea

    Sungkwan An

  3. Pritzker School of Medicine, Systems Biology Program, NUHS, University of Chicago, Evanston, IL, USA

    Mutsuko Ouchi & Toru Ouchi

  4. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Mutsuko Ouchi & Toru Ouchi

  5. VA Boston Healthcare System, Boston, MA, 02130, USA

    Neil Kowall, Junghee Lee & Hoon Ryu

  6. Boston University Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA, 02118, USA

    Neil Kowall, Junghee Lee & Hoon Ryu

  7. Department of Neurology, Boston University School of Medicine, 150 South Huntington Ave., Boston, MA, 02118, USA

    Neil Kowall, Junghee Lee & Hoon Ryu

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  1. Gye Sun Jeon
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Correspondence to Hoon Ryu.

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Jeon, G.S., Kim, K.Y., Hwang, Y.J. et al. Deregulation of BRCA1 Leads to Impaired Spatiotemporal Dynamics of γ-H2AX and DNA Damage Responses in Huntington’s Disease. Mol Neurobiol 45, 550–563 (2012). https://doi.org/10.1007/s12035-012-8274-9

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