C. elegans CEP-1/p53 and BEC-1 are involved in DNA repair
Sandy Hoffman1, Daniel Martin2, Alicia Meléndez3
1Department 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.
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.
Insights
The C. elegans p53 homolog, cep-1, is crucial for DNA repair and germline cell death following UVC radiation. DMC induces cep-1-independent cell death, and bec-1 interacts with cep-1 to protect the genome.
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- p53 is a critical transcription factor regulating cellular stress responses and acting as a tumor suppressor in mammals.
- The C. elegans p53 homolog, cep-1, controls DNA-damage-induced germline cell death by activating egl-1 and ced-13.
- Understanding p53's role in DNA repair and cell death across different damage types is essential.
Purpose of the Study:
- To investigate p53-dependent and p53-independent cell death and DNA repair pathways in response to distinct DNA damage in C. elegans.
- To examine the role of cep-1 in DNA lesion removal and its impact on progeny viability.
- To explore the interplay between cep-1, DNA damage, and germline tumor development.
Main Methods:
- Induction of DNA damage using ultraviolet C (UVC) radiation and 10-decarbamoyl mitomycin C (DMC).
- Assay of germline cell death and DNA lesions in wild-type and cep-1 loss-of-function mutant C. elegans.
- Analysis of germline tumor mutants (glp-1) treated with UVC, with and without cep-1.
- Investigation of the effect of bec-1 knockdown on cep-1-mediated responses.
Main Results:
- Wild-type animals showed enhanced UVC-lesion removal compared to cep-1 mutants, which exhibited increased lesion retention and reduced progeny viability.
- DMC induced C. elegans germline cell death independently of cep-1, mirroring mammalian p53-independent pathways.
- UVC treatment reduced tumor size in glp-1 mutants by activating egl-1, an effect abrogated in cep-1 mutants.
- Partial bec-1 knockdown led to CEP-1-dependent germline cell death and increased DNA damage.
Conclusions:
- CEP-1 plays a vital role in DNA repair and UVC-induced germline cell death in C. elegans.
- Distinct DNA-damaging agents can trigger both p53-dependent and p53-independent cellular responses.
- Cross-talk between BEC-1 and CEP-1 pathways is crucial for protecting the C. elegans genome from damage.
Related Concept Videos
02:36DNA Damage Can Stall the Cell Cycle
02:36DNA Damage can Stall the Cell Cycle
01:38Nucleotide Excision Repair
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
01:08Nucleotide Excision Repair
01:08Nucleotide Excision Repair
01:54Base Excision Repair
The first step of...