Mammalian SNM1 is required for genome stability
Mammalian SNM1 is required for genome stability
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DOI：
10.1016/j.ymgme.2007.11.012
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发表时间：
2008-05-01
影响因子：
3.8
通讯作者：
Moses, R. E.
中科院分区：
文献类型：
--
作者：
Hemphill, A. W.;Bruun, D.;Moses, R. E.
在酿酒酵母中由SNM1编码的蛋白质已被证明在DNA链间交联（ICL）修复中特异性地起作用。SNM1有五种哺乳动物同源物，包括参与V（D）J重组的Artemis。从小鼠构建的细胞与破坏的Snm1基因是敏感的DNA链间交联剂，丝裂霉素（MMC），如所示的辐射形成增加后曝光。老鼠繁殖正常，寿命正常。然而，当Snm 1破坏与Fancd 2破坏相结合时，可以注意到部分围产期死亡，这在单独的纯合突变体中均未观察到。为了探索hSNM1及其同源物在人细胞ICL修复中的作用，我们在人成纤维细胞中使用siRNA耗竭，细胞存活和染色体径向作为MMC治疗后敏感性的终点。如通过两个终点检测到的，hSNM1的消耗增加了对ICL的敏感性，而Artemis的消耗则没有。因此，在ICL形成后，liSNM1在维持基因组稳定性方面是有活性的。为了评估hSNM1和其他ICL修复途径之间的上位关系，我们在Fanconi贫血（FA）细胞中耗尽了hSNM1，FA细胞对ICL天生敏感。FA细胞系中hSNM1的消耗产生对MMC的附加敏感性。此外，FANCD 2的单泛素化（FA途径的终点）不受正常细胞中hSNM1的消耗的干扰。因此，hSNM1似乎代表了基因组稳定性的第二条途径，与FA途径不同。(c)2007年爱思唯尔公司All rights reserved.
The protein encoded by SNM1 in Saccharomyces cerevisiae has been shown to act specifically in DNA interstrand crosslinks (ICL) repair. There are five mammalian homologs of SNM1, including Artemis, which is involved in V(D)J recombination. Cells from mice constructed with a disruption in the Snm1 gene are sensitive to the DNA interstrand crosslinker, mitomycin (MMC), as indicated by increased radial formation following exposure. The mice reproduce normally and have normal life spans. However, a partial perinatal lethality, not seen in either homozygous mutant alone, can be noted when the Snm1 disruption is combined with a Fancd2 disruption. To explore the role of hSNM1 and its homologs in ICL repair in human cells, we used siRNA depletion in human fibroblasts, with cell survival and chromosome radials as the end points for sensitivity following treatment with MMC. Depletion of hSNM1 increases sensitivity to ICLs as detected by both end points, while depletion of Artemis does not. Thus liSNM1 is active in maintenance of genome stability following ICL formation. To evaluate the epistatic relationship between hSNM1 and other ICL repair pathways, we depleted hSNM1 in Fanconi anemia (FA) cells, which are inherently sensitive to ICLs. Depletion of hSNM1 in an FA cell line produces additive sensitivity for MMC. Further, mono-ubiquitination of FANCD2, an endpoint of the FA pathway, is not disturbed by depletion of hSNM1 in normal cells. Thus, hSNM1 appears to represent a second pathway for genome stability, distinct from the FA pathway. (c) 2007 Elsevier Inc. All rights reserved.