The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage
The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage
复制标题
DOI：
10.1038/onc.2008.17
复制
发表时间：
2008-06-01
期刊：
影响因子：
8
通讯作者：
Stambrook, P. J.
中科院分区：
文献类型：
--
作者：
Bahassi, E. M.;Ovesen, J. L.;Stambrook, P. J.
细胞对双链 DNA 断裂的反应涉及蛋白质相互作用的复合体，这些蛋白质相互作用控制细胞周期检查点停滞和 DNA 损伤的修复。检查点激酶 Chk1 和 Chk2 磷酸化 hBRCA2 的羧基末端结构域，hBRCA2 是一种参与重组介导的 DNA 修复 (HRR) 和复制叉维持的蛋白质。缺乏 hBRCA2 的细胞对 DNA 损伤剂高度敏感。 Chk1 和 Chk2 激酶靶向的 hBRCA2 残基的磷酸化可调节其与 Rad51 的相互作用。此外，细胞系 lex1/lex2 缺乏含有磷酸化残基的羧基末端结构域，在暴露于紫外线或电离辐射 (IR) 处理后，不支持 Rad51 定位于核灶。数据显示，Chk1 对 Rad51 的磷酸化或 Chk1 或 Chk2 对 hBRCA2 羧基末端结构域的磷酸化在 Rad51 与 hBRCA2 的结合以及随后 Rad51 募集至 DNA 损伤位点中发挥着关键作用。虽然细胞中 Chk1 的耗尽会导致 Rad51 因复制停滞而失去核灶定位，但缺乏 Chk2 的细胞也表现出 Rad51 定位缺陷，但仅在存在双链 DNA 断裂的情况下，表明这些激酶中的每一种可能对 Rad51 核蛋白的形成有所不同。哀叹取决于细胞造成的 DNA 损伤的类型。
The cellular response to the introduction of double strand DNA breaks involves complexes of protein interactions that govern cell cycle checkpoint arrest and repair of the DNA lesions. The checkpoint kinases Chk1 and Chk2 phosphorylate the carboxy-terminal domain of hBRCA2, a protein involved in recombination-mediated DNA repair (HRR) and replication fork maintenance. Cells deficient in hBRCA2 are hypersensitive to DNA damaging agents. Phosphorylation of the residue in hBRCA2 targeted by the Chk1 and Chk2 kinases regulates its interaction with Rad51. Furthermore, the cell line lex1/lex2, which lacks the carboxy-terminal domain containing the phosphorylated residue, does not support localization of Rad51 to nuclear foci after exposure to UV or treatment with ionizing radiation (IR). The data show that either phosphorylation of Rad51 by Chk1 or phosphorylation of the carboxy-terminal domain of hBRCA2 by Chk1 or Chk2 plays a critical role in the binding of Rad51 to hBRCA2 and the subsequent recruitment of Rad51 to sites of DNA damage. While depletion of Chk1 from cells leads to loss of Rad51 localization to nuclear foci in response to replication arrest, cells lacking Chk2 also show a defect in Rad51 localization, but only in presence of double strand DNA breaks, indicating that each of these kinases may contribute somewhat differently to the formation of Rad51 nucleoprotein. laments depending on the type of DNA damage incurred by the cells.