Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Nat Struct Mol Biol. 2011 Jun 26;18(7):761-8. doi: 10.1038/nsmb.2078.
Protein ubiquitination is a crucial component of the DNA damage response. To study the mechanism of the DNA damage-induced ubiquitination pathway, we analyzed the impact of the loss of two E3 ubiquitin ligases, RNF8 and Chfr. Notably, DNA damage-induced activation of ATM kinase is suppressed in cells deficient in both RNF8 and Chfr (double-knockout, or DKO), and DKO mice develop thymic lymphomas that are nearly diploid but harbor clonal chromosome translocations. Moreover, DKO mice and cells are hypersensitive to ionizing radiation. We present evidence that RNF8 and Chfr synergistically regulate histone ubiquitination to control histone H4 Lys16 acetylation through MRG15-dependent acetyltransferase complexes. Through these complexes, RNF8 and Chfr affect chromatin relaxation and modulate ATM activation and DNA damage response pathways. Collectively, our findings demonstrate that two chromatin-remodeling factors, RNF8 and Chfr, function together to activate ATM and maintain genomic stability in vivo.
蛋白质泛素化是 DNA 损伤反应的一个关键组成部分。为了研究 DNA 损伤诱导的泛素化途径的机制，我们分析了两种 E3 泛素连接酶 RNF8 和 Chfr 缺失的影响。值得注意的是，在 RNF8 和 Chfr 均缺失的细胞（双敲除，或 DKO）中，DNA 损伤诱导的 ATM 激酶激活受到抑制，并且 DKO 小鼠会发展出几乎是二倍体的胸腺淋巴瘤，但携带克隆性染色体易位。此外，DKO 小鼠和细胞对电离辐射高度敏感。我们提供的证据表明，RNF8 和 Chfr 通过 MRG15 依赖性乙酰转移酶复合物协同调节组蛋白泛素化，以控制组蛋白 H4 Lys16 乙酰化。通过这些复合物，RNF8 和 Chfr 影响染色质松弛，并调节 ATM 激活和 DNA 损伤反应途径。总之，我们的研究结果表明，两种染色质重塑因子 RNF8 和 Chfr 协同作用以激活 ATM 并在体内维持基因组稳定性。
