Deregulation of BRCA1 leads to impaired spatiotemporal dynamics of γ-H2AX and DNA damage responses in Huntington's disease.
Deregulation of BRCA1 leads to impaired spatiotemporal dynamics of γ-H2AX and DNA damage responses in Huntington's disease.
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DOI：
10.1007/s12035-012-8274-9
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发表时间：
2012-06
影响因子：
5.1
通讯作者：
Ryu H
中科院分区：
文献类型：
--
作者：
Jeon GS;Kim KY;Hwang YJ;Jung MK;An S;Ouchi M;Ouchi T;Kowall N;Lee J;Ryu H
亨廷顿病(Huntington‘s disease，HD)是一种中年起病的常染色体显性遗传性神经退行性疾病，由亨廷顿(Huntingtin，Htt)基因第1外显子CAG重复扩增引起的非自主运动和进行性认知功能下降为特征。神经元DNA损伤是HD神经退行性变的主要特征之一，但目前尚不清楚它是如何发生的，也不知道它与Htt基因的三重重复序列扩增突变的关系。在这里，我们发现非磷酸化和磷酸化BRCA1水平的失衡有助于HD的DNA损伤反应。值得注意的是，在HD细胞系中，γ-H_2AX是一种将各种DNA损伤修复因子招募到包括BRCA1在内的损伤部位的分子成分，当DNA损伤时，其核焦点受到失调。BRCA1通过BRCT域与γ-H2AX特异性地相互作用，这种关联在HD中被降低。在HD细胞中，BRCA1过表达可恢复γ-H2AX的表达，而BRCA1基因敲除则降低了γ-H2AX向核质的时空传播。HD转基因(R6/2)小鼠纹状体神经元γ-H_2AX核分布异常与BRCA1+/−小鼠纹状体神经元表达异常相关。我们的数据表明，BRCA1是有效地将γ-H_2AX聚集到神经元DNA损伤部位所必需的。综上所述，BRCA1直接调控γ-H_2AX在遗传毒性应激下的时空动态，是HD神经元DNA损伤反应的分子标记物。
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 dysregulated 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 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, 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.