Abstract
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.
Highlights
The tumor suppressor protein p53 is a transcription factor involved in activating cell cycle arrest, apoptosis, autophagy, and DNA repair [1]
The loss of functional p53 often occurs in human tumors allowing for the survival of cells which lack proper DNA damage checkpoints, cell cycle arrest and cell death [40]. p53 is conserved in its activation of cell death in different lower organisms including C. elegans and Drosophila [2,3,41]
P53 in C. elegans is involved in ultraviolet C (UVC) mediated germline cell cycle arrest and the regulation of autophagy [24,42]
Summary
The tumor suppressor protein p53 is a transcription factor involved in activating cell cycle arrest, apoptosis, autophagy, and DNA repair [1]. We confirmed that UVC-induced DNA lesions activated CEP-1 target genes in wild-type animals, with the egl-1 and ced-13 induction levels increased in young adults, four hours post UVC treatment. After 50 and 100 J/m2 of UVC treatment, the glp-1(ar202gf) mutant animals had fewer nuclear DNA lesions than the cep-1(gk138); glp1(ar202gf) animals (Fig. 4A) To determine if this increase in DNA lesions correlated with the expected decrease in CEP-1 activity we scored for egl-1 fold induction. Wild-type animals had an increase in CED-1::GFP positive cells in bec-1 RNAi fed animals after UVC treatment while cep-1(gk138) mutant worms did not (Fig. 7B). This suggested that the partial bec-1 knockdown-induced germline cell death was dependent on the presence of CEP-1. This suggests a cross-talk between CEP-1 and BEC-1 in DNA repair to improve genomic stability
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