Deficiency in Bre1 impairs homologous recombination repair and cell cycle checkpoint response to radiation damage in mammalian cells.
Deficiency in Bre1 impairs homologous recombination repair and cell cycle checkpoint response to radiation damage in mammalian cells.
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DOI：
10.1667/rr2184.1
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发表时间：
2010-11
影响因子：
3.4
通讯作者：
Brown JM
中科院分区：
文献类型：
--
作者：
Chernikova SB;Dorth JA;Razorenova OV;Game JC;Brown JM
组蛋白H3赖氨酸79(H3K79me2)的Dot1依赖甲基化涉及组蛋白H 2B赖氨酸123的BRE1依赖的单素化，这一途径与酿酒酵母暴露于电离辐射后的存活有关。我们发现，哺乳动物中Bre1同源基因的缺失会损害对电离辐射的反应，导致辐射敏感性增加和G2/M检查点缺陷。Bre1a/b功能的缺陷还与小鼠细胞对交联剂的敏感性增加和RAD51焦点的缺陷形成有关，这表明在同源重组修复方面存在缺陷，类似于在酵母中看到的缺陷。在萌芽酵母中，H3K79me2对于将检查点信号蛋白Rad9招募到双链断裂(DSB)位点是重要的。然而，在哺乳动物细胞中，除了H3K79me2外，53BP1(Rad9同源基因)还识别另一个残基H4K20me2，一些研究认为53BP1的首选靶点是H4K20me2而不是H3K79me2。我们在这里表明，Bre1b的缺失特异性地减少了H3K79的二甲基化，而不影响H4K20的二甲基化。因此，我们的数据表明，观察到的Bre1a/b缺陷细胞辐射反应的缺陷与H3K79me2减少有关，而与H4K20me2无关。
The pathway involving Bre1-dependent monoubiquitination of histone H2B lysine 123, which leads to Dot1-dependent methylation of histone H3 lysine 79 (H3K79me2), has been implicated in survival after exposure to ionizing radiation in Saccharomyces cerevisiae. We found that depletion of mammalian homologs of Bre1 compromises the response to ionizing radiation, leading to increased radiosensitivity and a G2/M checkpoint defect. The deficiency in Bre1a/b function was also associated with increased sensitivity to crosslinking drugs and defective formation of Rad51 foci in mouse cells, suggesting a defect in homologous recombinational repair analogous to that seen in Saccharomyces. In budding yeast, H3K79me2 is important for the recruitment of the checkpoint signaling protein Rad9 to sites of double-strand breaks (DSBs). However, in mammalian cells, 53BP1 (the Rad9 ortholog) in addition to H3K79me2 recognizes a different residue, H4K20me2, and some studies argue that it is H4K20me2 and not H3K79me2 that is the preferred target for 53BP1. We show here that depletion of Bre1b specifically reduced dimethylation of H3K79 without affecting dimethylation of H4K20. Thus our data suggest that the observed defects in the radiation response of Bre1a/b-deficient cells are associated with reduced H3K79me2 and not with H4K20me2.