Translational repression of C. elegans p53 by GLD-1 regulates DNA damage-induced apoptosis.
p53 is a tumor suppressor gene whose regulation is crucial to maintaining genome stability and for the apoptotic elimination of abnormal, potentially cancer-predisposing cells. C. elegans contains a primordial p53 gene, cep-1, that acts as a transcription factor necessary for DNA damage-induced apoptosis. In a genetic screen for negative regulators of CEP-1, we identified a mutation in GLD-1, a translational repressor implicated in multiple C. elegans germ cell fate decisions and related to mammalian Quaking proteins. CEP-1-dependent transcription of proapoptotic genes is upregulated in the gld-1(op236) mutant and an elevation of p53-mediated germ cell apoptosis in response to DNA damage is observed. Further, we demonstrate that GLD-1 mediates its repressive effect by directly binding to the 3'UTR of cep-1/p53 mRNA and repressing its translation. This study reveals that the regulation of cep-1/p53 translation influences DNA damage-induced apoptosis and demonstrates the physiological importance of this mechanism.
Schumacher
Björn
B
Department of Cell Biology, Max-Planck-Institute for Biochemistry, Am Klopferspitz 18a, D 82152 Martinsried, Germany.
Hanazawa
Momoyo
M
Lee
Min-Ho
MH
Nayak
Sudhir
S
Volkmann
Katrin
K
Hofmann
E Randal
ER
Hofmann
Randall
R
Hengartner
Michael
M
Schedl
Tim
T
Gartner
Anton
A
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001665:Binding Sites / Q000502:physiology; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012733:Sex Differentiation / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D020413:3' Untranslated Regions; C438244:CEP-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; C094448:GLD-1 protein, C elegans; D012333:RNA, Messenger; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53