Hofmann E Randal, Milstein Stuart, Boulton Simon J, Ye Mianjia, Hofmann Jen J, Stergiou Lilli, Gartner Anton, Vidal Marc, Hengartner Michael O
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Curr Biol. 2002 Nov 19;12(22):1908-18. doi: 10.1016/s0960-9822(02)01262-9.
The inability to efficiently repair DNA damage or remove cells with severely damaged genomes has been linked to several human cancers. Studies in yeasts and mammals have identified several genes that are required for proper activation of cell cycle checkpoints following various types of DNA damage. However, in metazoans, DNA damage can induce apoptosis as well. How DNA damage activates the apoptotic machinery is not fully understood.
We demonstrate here that the Caenorhabditis elegans gene hus-1 is required for DNA damage-induced cell cycle arrest and apoptosis. Following DNA damage, HUS-1 relocalizes and forms distinct foci that overlap with chromatin. Relocalization does not require the novel checkpoint protein RAD-5; rather, relocalization appears more frequently in rad-5 mutants, suggesting that RAD-5 plays a role in repair. HUS-1 is required for genome stability, as demonstrated by increased frequency of spontaneous mutations, chromosome nondisjunction, and telomere shortening. Finally, we show that DNA damage increases expression of the proapoptotic gene egl-1, a response that requires hus-1 and the p53 homolog cep-1.
Our findings suggest that the RAD-5 checkpoint protein is not required for HUS-1 to relocalize following DNA damage. Furthermore, our studies reveal a new function of HUS-1 in the prevention of telomere shortening and mortalization of germ cells. DNA damage-induced germ cell death is abrogated in hus-1 mutants, in part, due to the inability of these mutants to activate egl-1 transcription in a cep-1/p53-dependent manner. Thus, HUS-1 is required for p53-dependent activation of a BH3 domain protein in C. elegans.
无法有效修复DNA损伤或清除基因组严重受损的细胞与多种人类癌症相关。对酵母和哺乳动物的研究已鉴定出几种基因，这些基因是在各种类型的DNA损伤后正确激活细胞周期检查点所必需的。然而，在后生动物中，DNA损伤也可诱导细胞凋亡。DNA损伤如何激活凋亡机制尚不完全清楚。
我们在此证明，秀丽隐杆线虫基因hus-1是DNA损伤诱导的细胞周期停滞和细胞凋亡所必需的。DNA损伤后，HUS-1重新定位并形成与染色质重叠的独特焦点。重新定位不需要新的检查点蛋白RAD-5；相反，重新定位在rad-5突变体中更频繁出现，表明RAD-5在修复中起作用。HUS-1是基因组稳定性所必需的，这通过自发突变、染色体不分离和端粒缩短频率的增加得到证明。最后，我们表明DNA损伤增加了促凋亡基因egl-1的表达，这种反应需要hus-1和p53同源物cep-1。
我们的研究结果表明，DNA损伤后HUS-1重新定位不需要RAD-5检查点蛋白。此外，我们的研究揭示了HUS-1在预防端粒缩短和生殖细胞衰老方面的新功能。hus-1突变体中DNA损伤诱导的生殖细胞死亡被消除，部分原因是这些突变体无法以cep-1/p53依赖的方式激活egl-1转录。因此，秀丽隐杆线虫中p53依赖的BH3结构域蛋白激活需要HUS-1。
