C. elegans CEP-1/p53 and BEC-1 are involved in DNA repair.
C. elegans CEP-1/p53 and BEC-1 are involved in DNA repair.
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DOI：
10.1371/journal.pone.0088828
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Bargonetti J
中科院分区：
文献类型：
--
作者：
Hoffman S;Martin D;Meléndez A;Bargonetti J
P53是一种调节细胞应激反应的转录因子。哺乳动物p53是一种肿瘤抑制因子。秀丽隐杆线虫的p53， cep-1，通过激活egl-1和ced-13的转录来调节dna损伤诱导的种系细胞死亡。我们使用秀丽隐杆线虫模型来研究在整个动物中，不同形式的DNA损伤如何诱导p53依赖性与p53非依赖性的细胞死亡和DNA修复。紫外线C型（UVC）辐射或10-decarbamoyl丝裂霉素C （DMC，一种已知可诱导哺乳动物p53非依赖性细胞死亡的药物）诱导DNA损伤。检测野生型或cep-1功能丧失突变动物的种系细胞死亡和DNA损伤。随着时间的推移，野生型动物显示出更多的uvc病变清除，而cep-1突变动物显示出增加的uvc病变保留。cep-1突变增加uvc病变保留与后代生存能力降低直接相关。与DMC诱导哺乳动物细胞不依赖p53的细胞死亡一致，DMC诱导秀丽隐杆线虫不依赖p53的生殖系细胞死亡途径。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glp-1(ar202gf)/Notch种系肿瘤突变体。UVC处理glp-1突变动物激活了CEP-1靶基因egl-1，减小了肿瘤大小。在cep-1 (gk138);glp-1（ar202gf）动物，UVC治疗导致对病变的易感性增加和肿瘤种系增大。有趣的是，在成人中部分敲低bec1导致cep -1依赖性生殖细胞死亡增加和DNA损伤增加。这些结果有力地支持了bc -1和CEP-1之间的串扰以保护秀丽隐杆线虫的基因组。
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.
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