BMI1 Is Recruited to DNA Breaks and Contributes to DNA Damage-Induced H2A Ubiquitination and Repair
BMI1 Is Recruited to DNA Breaks and Contributes to DNA Damage-Induced H2A Ubiquitination and Repair
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DOI：
10.1128/mcb.00981-10
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发表时间：
2011-05-01
影响因子：
5.3
通讯作者：
Ganesan, Shridar
中科院分区：
文献类型：
--
作者：
Ginjala, Vasudeva;Nacerddine, Karim;Ganesan, Shridar
DNA损伤激活了导致局部染色质修饰和DNA修复蛋白募集的信号通路。具有泛素连接酶活性的多种DNA修复蛋白被招募到DNA损伤位点，在那里它们泛素化组蛋白和其他底物。这种DNA损伤诱导的组蛋白泛素化被认为在介导DNA损伤反应中起关键作用。我们现在报道，多梳蛋白BMI1被迅速招募到DNA损伤位点，在那里它持续超过8小时。BMI1在损伤位点的持续定位依赖于完整的ATM和ATR，需要H2AX磷酸化和RNF8的招募。BMI1是DNA损伤诱导的赖氨酸119处组蛋白H2A泛素化所必需的。BMI1的缺失导致同源重组对DNA双链断裂的修复受损，细胞在G(2)/M中积累。这些数据支持BMI1在细胞对DNA损伤的反应中起关键作用。
DNA damage activates signaling pathways that lead to modification of local chromatin and recruitment of DNA repair proteins. Multiple DNA repair proteins having ubiquitin ligase activity are recruited to sites of DNA damage, where they ubiquitinate histones and other substrates. This DNA damage-induced histone ubiquitination is thought to play a critical role in mediating the DNA damage response. We now report that the polycomb protein BMI1 is rapidly recruited to sites of DNA damage, where it persists for more than 8 h. The sustained localization of BMI1 to damage sites is dependent on intact ATM and ATR and requires H2AX phosphorylation and recruitment of RNF8. BMI1 is required for DNA damage-induced ubiquitination of histone H2A at lysine 119. Loss of BMI1 leads to impaired repair of DNA double-strand breaks by homologous recombination and the accumulation of cells in G(2)/M. These data support a crucial role for BMI1 in the cellular response to DNA damage.