Molecular Neurobiology

, Volume 45, Issue 3, pp 550–563

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

  • Gye Sun Jeon
  • Ki Yoon Kim
  • Yu Jin Hwang
  • Min-Kyung Jung
  • Sungkwan An
  • Mutsuko Ouchi
  • Toru Ouchi
  • Neil Kowall
  • Junghee Lee
  • Hoon Ryu
Article

DOI: 10.1007/s12035-012-8274-9

Cite this article as:
Jeon, G.S., Kim, K.Y., Hwang, Y.J. et al. Mol Neurobiol (2012) 45: 550. doi:10.1007/s12035-012-8274-9

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.

Keywords

DNA damage BRCA1 H2AX Neurodegeneration Huntington’s disease 

Supplementary material

12035_2012_8274_MOESM1_ESM.doc (212 kb)
ESM 1(DOC 211 kb)

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Gye Sun Jeon
    • 1
  • Ki Yoon Kim
    • 1
  • Yu Jin Hwang
    • 1
  • Min-Kyung Jung
    • 1
  • Sungkwan An
    • 2
  • Mutsuko Ouchi
    • 3
    • 4
  • Toru Ouchi
    • 3
    • 4
  • Neil Kowall
    • 5
    • 6
    • 7
  • Junghee Lee
    • 5
    • 6
    • 7
  • Hoon Ryu
    • 1
    • 5
    • 6
    • 7
  1. 1.WCU Neurocytomics Group, Department of Biomedical SciencesSeoul National University College of MedicineSeoulSouth Korea
  2. 2.Department of Microbial Engineering, Functional Genoproteome Research CenterKonkuk UniversitySeoulSouth Korea
  3. 3.Pritzker School of Medicine, Systems Biology Program, NUHSUniversity of ChicagoEvanstonUSA
  4. 4.Department of Cancer GeneticsRoswell Park Cancer InstituteBuffaloUSA
  5. 5.VA Boston Healthcare SystemBostonUSA
  6. 6.Boston University Alzheimer’s Disease CenterBoston University School of MedicineBostonUSA
  7. 7.Department of NeurologyBoston University School of MedicineBostonUSA