Stergiou L, Doukoumetzidis K, Sendoel A, Hengartner M O
Institute of Molecular Biology, University of Zurich, Winterthurerstrasse, Zurich, Switzerland.
Cell Death Differ. 2007 Jun;14(6):1129-38. doi: 10.1038/sj.cdd.4402115. Epub 2007 Mar 9.
Ultraviolet (UV) radiation is a mutagen of major clinical importance in humans. UV-induced damage activates multiple signaling pathways, which initiate DNA repair, cell cycle arrest and apoptosis. To better understand these pathways, we studied the responses to UV-C light (254 nm) of germ cells in Caenorhabditis elegans. We found that UV activates the same cellular responses in worms as in mammalian cells. Both UV-induced apoptosis and cell cycle arrest were completely dependent on the p53 homolog CEP-1, the checkpoint proteins HUS-1 and CLK-2, and the checkpoint kinases CHK-2 and ATL-1 (the C. elegans homolog of ataxia telangiectasia and Rad3-related); ATM-1 (ataxia telangiectasia mutated-1) was also required, but only at low irradiation doses. Importantly, mutation of genes encoding nucleotide excision repair pathway components severely disrupted both apoptosis and cell cycle arrest, suggesting that these genes not only participate in repair, but also signal the presence of damage to downstream components of the UV response pathway that we delineate here. Our study suggests that whereas DNA damage response pathways are conserved in metazoans in their general outline, there is significant evolution in the relative importance of individual checkpoint genes in the response to specific types of DNA damage.
紫外线（UV）辐射是对人类具有重要临床意义的诱变剂。紫外线诱导的损伤会激活多种信号通路，从而启动DNA修复、细胞周期停滞和细胞凋亡。为了更好地理解这些通路，我们研究了秀丽隐杆线虫生殖细胞对紫外线C光（254纳米）的反应。我们发现，紫外线在蠕虫中激活的细胞反应与在哺乳动物细胞中相同。紫外线诱导的细胞凋亡和细胞周期停滞都完全依赖于p53同源物CEP-1、检查点蛋白HUS-1和CLK-2，以及检查点激酶CHK-2和ATL-1（共济失调毛细血管扩张症和Rad3相关蛋白的秀丽隐杆线虫同源物）；ATM-1（共济失调毛细血管扩张症突变体-1）也是必需的，但仅在低辐射剂量下。重要的是，编码核苷酸切除修复途径成分的基因突变严重破坏了细胞凋亡和细胞周期停滞，这表明这些基因不仅参与修复，还向我们在此描述的紫外线反应途径的下游成分发出损伤信号。我们的研究表明，虽然后生动物的DNA损伤反应通路在总体轮廓上是保守的，但在对特定类型DNA损伤的反应中，各个检查点基因的相对重要性存在显著进化。
