Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, Zurich, Switzerland.
Cell Death Differ. 2011 May;18(5):897-906. doi: 10.1038/cdd.2010.158. Epub 2010 Dec 10.
Ultraviolet (UV) radiation-induced DNA damage evokes a complex network of molecular responses, which culminate in DNA repair, cell cycle arrest and apoptosis. Here, we provide an in-depth characterization of the molecular pathway that mediates UV-C-induced apoptosis of meiotic germ cells in the nematode Caenorhabditis elegans. We show that UV-C-induced DNA lesions are not directly pro-apoptotic. Rather, they must first be recognized and processed by the nucleotide excision repair (NER) pathway. Our data suggest that NER pathway activity transforms some of these lesions into other types of DNA damage, which in turn are recognized and acted upon by the homologous recombination (HR) pathway. HR pathway activity is in turn required for the recruitment of the C. elegans homolog of the yeast Rad9-Hus1-Rad1 (9-1-1) complex and activation of downstream checkpoint kinases. Blocking either the NER or HR pathway abrogates checkpoint pathway activation and UV-C-induced apoptosis. Our results show that, following UV-C, multiple DNA repair pathways can cooperate to signal to the apoptotic machinery to eliminate potentially hazardous cells.
紫外线 (UV) 辐射诱导的 DNA 损伤会引发复杂的分子反应网络，最终导致 DNA 修复、细胞周期停滞和细胞凋亡。在这里，我们深入描述了介导线虫秀丽隐杆线虫减数分裂生殖细胞中 UV-C 诱导细胞凋亡的分子途径。我们表明，UV-C 诱导的 DNA 损伤本身并不是直接促凋亡的。相反，它们必须首先被核苷酸切除修复 (NER) 途径识别和处理。我们的数据表明，NER 途径活性将这些损伤中的一些转化为其他类型的 DNA 损伤，而这些损伤反过来又被同源重组 (HR) 途径识别和作用。HR 途径活性反过来又需要招募酵母 Rad9-Hus1-Rad1 (9-1-1) 复合物的秀丽隐杆线虫同源物，并激活下游检查点激酶。阻断 NER 或 HR 途径会阻断检查点途径的激活和 UV-C 诱导的细胞凋亡。我们的结果表明，在 UV-C 之后，多种 DNA 修复途径可以协同作用，向凋亡机制发出信号，以消除潜在的危险细胞。
