Histone Ubiquitination Associates with BRCA1-Dependent DNA Damage Response
Histone Ubiquitination Associates with BRCA1-Dependent DNA Damage Response
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DOI：
10.1128/mcb.01302-08
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发表时间：
2009-02-01
影响因子：
5.3
通讯作者：
Yu, Xiaochun
中科院分区：
文献类型：
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作者：
Wu, Jiaxue;Huen, Michael S. Y.;Yu, Xiaochun
组蛋白泛素化参与多种细胞过程，包括DNA损伤反应。然而，其中涉及的分子机制尚不清楚。在这里，我们已经确定了BRCA1的功能伙伴RAP80/UIMC1(泛素相互作用基序包含1)识别泛素化的组蛋白H_2A和H_2B。RAP80与泛素化的组蛋白H_2A和H_2B之间的相互作用在DNA损伤后增加。由于RAP80促进了BRCA1的S易位到DNA损伤部位，我们的结果表明泛素化的组蛋白H_2A和H_2B可能是DNA损伤反应中BRCA1/RAP80复合体的上游伙伴。此外，我们还发现E3泛素连接酶RNF8(Ring Finger Protein 8)调节组蛋白H_2A和H_2B的泛素化。在RNF8缺陷的小鼠胚胎成纤维细胞中，组蛋白H_2A和H_2B的泛素化显著降低，从而消除了DNA损伤导致的BRCA1和RAP80在染色质损伤处的积聚。综上所述，我们的结果表明泛素化的组蛋白H_2A和H_2B可能招募BRCA1复合体来损伤染色质上的DNA。
Histone ubiquitination participates in multiple cellular processes, including the DNA damage response. However, the molecular mechanisms involved are not clear. Here, we have identified that RAP80/UIMC1 (ubiquitin interaction motif containing 1), a functional partner of BRCA1, recognizes ubiquitinated histones H2A and H2B. The interaction between RAP80 and ubiquitinated histones H2A and H2B is increased following DNA damage. Since RAP80 facilitates BRCA1's translocation to DNA damage sites, our results indicate that ubiquitinated histones H2A and H2B could be upstream partners of the BRCA1/RAP80 complex in the DNA damage response. Moreover, we have found that RNF8 (ring finger protein 8), an E3 ubiquitin ligase, regulates ubiquitination of both histones H2A and H2B. In RNF8-deficient mouse embryo fibroblasts, ubiquitination of both histones H2A and H2B is dramatically reduced, which abolishes the DNA damage-induced BRCA1 and RAP80 accumulation at damage lesions on the chromatin. Taken together, our results suggest that ubiquitinated histones H2A and H2B may recruit the BRCA1 complex to DNA damage lesions on the chromatin.