Dataset Information

Deregulation of BRCA1 leads to impaired spatiotemporal dynamics of ?-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 ?-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 ?-H2AX via the BRCT domain, and this association was reduced in HD. BRCA1 overexpression restored ?-H2AX level in the nucleus of HD cells, while BRCA1 knockdown reduced the spatiotemporal propagation of ?-H2AX foci to the nucleoplasm. The deregulation of BRCA1 correlated with an abnormal nuclear distribution of ?-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 ?-H2AX to the sites of neuronal DNA damage. Taken together, our results show that BRCA1 directly modulates the spatiotemporal dynamics of ?-H2AX upon genotoxic stress and serves as a molecular maker for neuronal DNA damage response in HD.

SUBMITTER: Jeon GS

PROVIDER: S-EPMC4642996 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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

Jeon Gye Sun GS Kim Ki Yoon KY Hwang Yu Jin YJ Jung Min-Kyung MK An Sungkwan S Ouchi Mutsuko M Ouchi Toru T Kowall Neil N Lee Junghee J Ryu Hoon H

Molecular neurobiology 20120513 3

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 phosphorylat ...[more]

PMID: 22580959

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Project description:The response of cells to ionizing radiation-induced DNA double-strand breaks (DSB) is determined by the activation of multiple pathways aimed at repairing the injury and maintaining genomic integrity. Densely ionizing radiation induces complex damage consisting of different types of DNA lesions in close proximity that are difficult to repair and may promote carcinogenesis. Little is known about the dynamic behavior of repair proteins on complex lesions. In this study we use live-cell imaging for the spatio-temporal characterization of early protein interactions at damage sites of increasing complexity. Beamline microscopy was used to image living cells expressing fluorescently-tagged proteins during and immediately after charged particle irradiation to reveal protein accumulation at damaged sites in real time. Information on the mobility and binding rates of the recruited proteins was obtained from fluorescence recovery after photobleaching (FRAP). Recruitment of the DNA damage sensor protein NBS1 accelerates with increasing lesion density and saturates at very high damage levels. FRAP measurements revealed two different binding modalities of NBS1 to damage sites and a direct impact of lesion complexity on the binding. Faster recruitment with increasing lesion complexity was also observed for the mediator MDC1, but mobility was limited at very high damage densities due to nuclear-wide binding. We constructed a minimal computer model of the initial response to DSB based on known protein interactions only. By fitting all measured data using the same set of parameters, we can reproduce the experimentally characterized steps of the DNA damage response over a wide range of damage densities. The model suggests that the influence of increasing lesion density accelerating NBS1 recruitment is only dependent on the different binding modes of NBS1, directly to DSB and to the surrounding chromatin via MDC1. This elucidates an impact of damage clustering on repair without the need of invoking extra processing steps.

Dataset Information

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

Publications

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

Similar Datasets

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