D'Amours D, Jackson S P
Wellcome Trust and Cancer Research Campaign Institute of Cancer and Developmental Biology, and Department of Zoology, University of Cambridge, CB2 1QR Cambridge, UK.
Genes Dev. 2001 Sep 1;15(17):2238-49. doi: 10.1101/gad.208701.
The Nbs1 complex is an evolutionarily conserved multisubunit nuclease composed of the Mre11, Rad50, and Nbs1 proteins. Hypomorphic mutations in the NBS1 or MRE11 genes in humans result in conditions characterized by DNA damage sensitivity, cell cycle checkpoint deficiency, and high cancer incidence. The equivalent complex in the yeast Saccharomyces cerevisiae (Xrs2p complex) has been implicated in DNA double-strand break repair and in telomere length regulation. Here, we find that xrs2Delta, mre11Delta, and rad50Delta mutants are markedly defective in the initiation of the intra-S phase checkpoint in response to DNA damage. Furthermore, the absence of a functional Xrs2p complex leads to sensitivity to deoxynucleotide depletion and to an inability to efficiently slow down cell cycle progression in response to hydroxyurea. The checkpoint appears to require the nuclease activity of Mre11p and its defect is associated with the abrogation of the Tel1p/Mec1p signaling pathway. Notably, DNA damage induces phosphorylation of both Xrs2p and Mre11p in a Tel1p-dependent manner. These results indicate that the Tel1p/ATM signaling pathway is conserved from yeast to humans and suggest that the Xrs2p/Nbs1 complexes act as signal modifiers.
Nbs1复合物是一种进化上保守的多亚基核酸酶，由Mre11、Rad50和Nbs1蛋白组成。人类NBS1或MRE11基因的亚效突变导致以DNA损伤敏感性、细胞周期检查点缺陷和高癌症发病率为特征的病症。酿酒酵母中的等效复合物（Xrs2p复合物）已被证明参与DNA双链断裂修复和端粒长度调节。在这里，我们发现xrs2Δ、mre11Δ和rad50Δ突变体在响应DNA损伤时启动S期内检查点方面存在明显缺陷。此外，缺乏功能性Xrs2p复合物会导致对脱氧核苷酸耗竭敏感，并导致无法有效减缓细胞周期进程以响应羟基脲。该检查点似乎需要Mre11p的核酸酶活性，其缺陷与Tel1p/Mec1p信号通路的废除有关。值得注意的是，DNA损伤以Tel1p依赖的方式诱导Xrs2p和Mre11p的磷酸化。这些结果表明Tel1p/ATM信号通路从酵母到人类都是保守的，并表明Xrs2p/Nbs1复合物作为信号调节剂起作用。
