Cancer Institute of New Jersey, Robert Wood Johnson Medical School-UMDNJ, New Brunswick, New Jersey, USA.
Mol Cell Biol. 2011 May;31(10):1972-82. doi: 10.1128/MCB.00981-10. Epub 2011 Mar 7.
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.
DNA 损伤激活信号通路，导致局部染色质的修饰和 DNA 修复蛋白的募集。多种具有泛素连接酶活性的 DNA 修复蛋白被募集到 DNA 损伤部位，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 损伤反应中起着关键作用。我们现在报告说，多梳蛋白 BMI1 被迅速募集到 DNA 损伤部位，在那里它持续存在超过 8 小时。BMI1 持续定位到损伤部位依赖于完整的 ATM 和 ATR，需要 H2AX 磷酸化和 RNF8 的募集。BMI1 是 DNA 损伤诱导的组蛋白 H2A 赖氨酸 119 泛素化所必需的。BMI1 的缺失导致同源重组修复 DNA 双链断裂的能力受损，并导致细胞在 G2/M 期积累。这些数据支持 BMI1 在细胞对 DNA 损伤的反应中的关键作用。
