The SCF FSN-1 ubiquitin ligase controls germline apoptosis through CEP-1/p53 in C. elegans.
The nematode Caenorhabditis elegans contains a single ancestral p53 family member, cep-1, which is required to activate apoptosis of germ cells in response to DNA damage. To understand how the cep-1/p53 pathway is regulated in response to genotoxic stress, we performed an RNA interference screen and identified the neddylation pathway and components of an SCF (Skp1/cullin/F-box) E3 ubiquitin ligase as negative regulators of cep-1-dependent germ cell apoptosis. Here, we show that the cullin gene cul-1, the Skp1-related gene skr-1, and the ring box genes rbx-1 and rpm-1 all negatively regulate cep-1-dependent germ cell apoptosis in response to the DNA-alkylating agent N-ethyl-N-nitrosourea (ENU). We also identified the F-box protein FSN-1, previously shown to form an SCF ligase that regulates synapse development, as a negative regulator of cep-1-dependent germline apoptosis. The hypersensitivity of fsn-1 mutants to ENU-induced germline apoptosis was completely suppressed by a cep-1 loss-of-function allele. We further provide evidence that the transcriptional activity, phosphorylation status, and levels of endogenous CEP-1 are higher in fsn-1 mutants compared with wild-type animals after ENU treatment. Our results uncover a novel role for the SCF(FSN-1) E3 ubiquitin ligase in the regulation of cep-1-dependent germ cell apoptosis.
Gao
M X
MX
Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto Medical Discovery Tower, 101 College Street, Toronto, Ontario, Canada.
Liao
E H
EH
Yu
B
B
Wang
Y
Y
Zhen
M
M
Derry
W B
WB
D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D004249:DNA Damage; D044783:F-Box Proteins / Q000235:genetics / Q000502:physiology*; D005854:Germ Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D009154:Mutation; D000075687:NEDD8 Protein; D034622:RNA Interference; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
C438244:CEP-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D044783:F-Box Proteins; C530278:FSN-1 protein, C elegans; C546714:NED-8 protein, C elegans; D000075687:NEDD8 Protein; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; D044843:SKP Cullin F-Box Protein Ligases