Department of Biological Sciences, Hunter College, City University of New York, New York City, New York, United States of America ; The Graduate Center Departments of Biology and Biochemistry, City University of New York, New York City, New York, United States of America.
Department of Biological Sciences, Hunter College, City University of New York, New York City, New York, United States of America.
PLoS One. 2014 Feb 20;9(2):e88828. doi: 10.1371/journal.pone.0088828. eCollection 2014.
p53 is a transcription factor that regulates the response to cellular stress. Mammalian p53 functions as a tumor suppressor. The C. elegans p53, cep-1, regulates DNA-damage induced germline cell death by activating the transcription of egl-1 and ced-13. We used the C. elegans model to investigate how, in the whole animal, different forms of DNA damage can induce p53-dependent versus p53-independent cell death and DNA repair. DNA damage was induced by ultraviolet type C (UVC) radiation, or 10-decarbamoyl mitomycin C (DMC, an agent known to induce mammalian p53-independent cell death). Wild-type or cep-1 loss-of-function mutant animals were assayed for germline cell death and DNA lesions. Wild-type animals displayed greater removal of UVC-lesions over time, whereas cep-1 mutant animals displayed increased UVC-lesion retention. The cep-1 mutation increased UVC-lesion retention directly correlated with a reduction of progeny viability. Consistent with DMC inducing p53-independent cell death in mammalian cells DMC induced a C. elegans p53-independent germline cell death pathway. To examine the influence of wild-type CEP-1 and DNA damage on C. elegans tumors we used glp-1(ar202gf)/Notch germline tumor mutants. UVC treatment of glp-1 mutant animals activated the CEP-1 target gene egl-1 and reduced tumor size. In cep-1(gk138);glp-1(ar202gf) animals, UVC treatment resulted in increased susceptibility to lesions and larger tumorous germlines. Interestingly, the partial knockdown of bec-1 in adults resulted in a CEP-1-dependent increase in germline cell death and an increase in DNA damage. These results strongly support cross-talk between BEC-1 and CEP-1 to protect the C. elegans genome.
p53 是一种转录因子，可调节细胞应激反应。哺乳动物 p53 作为肿瘤抑制因子发挥作用。秀丽隐杆线虫中的 p53，cep-1，通过激活 egl-1 和 ced-13 的转录来调节 DNA 损伤诱导的生殖细胞死亡。我们使用秀丽隐杆线虫模型来研究在整个动物体内，不同形式的 DNA 损伤如何诱导依赖 p53 和不依赖 p53 的细胞死亡和 DNA 修复。通过紫外线 C（UVC）辐射或 10-脱甲酰基丝裂霉素 C（DMC，一种已知诱导哺乳动物不依赖 p53 的细胞死亡的药物）诱导 DNA 损伤。对野生型或 cep-1 功能丧失突变体动物进行生殖细胞死亡和 DNA 损伤检测。野生型动物随着时间的推移显示出 UVC 损伤的清除增加，而 cep-1 突变体动物显示出 UVC 损伤的保留增加。cep-1 突变导致 UVC 损伤的保留直接与后代活力的降低相关。与 DMC 在哺乳动物细胞中诱导不依赖 p53 的细胞死亡一致，DMC 诱导了秀丽隐杆线虫中不依赖 p53 的生殖细胞死亡途径。为了研究野生型 CEP-1 和 DNA 损伤对秀丽隐杆线虫肿瘤的影响，我们使用了 glp-1(ar202gf)/Notch 生殖细胞肿瘤突变体。UVC 处理 glp-1 突变动物激活了 CEP-1 的靶基因 egl-1，并减少了肿瘤大小。在 cep-1(gk138);glp-1(ar202gf)动物中，UVC 处理导致易受损伤和更大的肿瘤生殖细胞的敏感性增加。有趣的是，成年动物中 bec-1 的部分敲低导致依赖 CEP-1 的生殖细胞死亡增加和 DNA 损伤增加。这些结果强烈支持 BEC-1 和 CEP-1 之间的交叉对话，以保护秀丽隐杆线虫的基因组。
