Translational Repression of C. elegans p53 by GLD-1 Regulates DNA Damage-Induced Apoptosis

Abstract

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.

Translational Control in the Caenorhabditis elegans Germ Line

“…It is also conceivable that the mechanism of GLD-1-mediated translational repression depends on the target mRNA and its associated factors. This is further underscored by mutations in GLD-1 that affect the regulation of a few mRNA targets but not others (Schumacher et al 2005 ) . Given that a large number of veri fi ed GLD-1 target mRNAs encode proteins involved in diverse biological roles (see Table 8.5 ), the importance of GLD-1 for germline development is easy to comprehend.…”

“…Given that a large number of veri fi ed GLD-1 target mRNAs encode proteins involved in diverse biological roles (see Table 8.5 ), the importance of GLD-1 for germline development is easy to comprehend. It regulates the balance of proliferation vs. meiotic entry (Hansen et al 2004 ) , female meiotic progression (Francis et al 1995a, b ) , physiological apoptosis (Schumacher et al 2005 ) , the sperm-to-oocyte switch (Jan et al 1999 ) , and maintenance of germ cell totipotency (Ciosk et al 2006 ) .…”

“…Consequently, much more focused genetic screens are required (Schumacher et al 2005 ) and biochemical approaches combined with modern molecular detection systems need to be pursued Kershner and Kimble 2010 ;Wright et al 2011 ) . Although this is not limited to C. elegans , as most RNA-binding selector proteins in all species will have multiple targets, a few target mRNAs were identi fi ed in such screens by mutations that clustered in 3 ¢ UTRs.…”

An Extended RNA Binding Site for the Yeast Branch Point-binding Protein and the Role of Its Zinc Knuckle Domains in RNA Binding

“…GLD-1, another STAR/GSG protein, also has a binding site (UACU(A/C)A) that is almost identical to the BPS (55,56). GLD-1 is a Caenorhabditis elegans protein involved in germ line development and apoptosis that represses translation of such mRNAs as tra-2 and cep-1/p53 (57)(58)(59)(60). GLD-1 and BBP also have a 70% sequence identity and 85% sequence similarity in their RNA binding amino acids.…”

Lessons from p53 in non-mammalian models

“…For example, an ATR ortholog in C. elegans, atl-1, also triggers apoptosis via cep-1/ egl-1 pathway after radiation. 16 Other recently reported p53 regulators in C. elegans such as GLD-1 17 and iASPP 18 have not been examined in other systems. While the ATM/ATR mode of regulation appears well conserved here, it is not yet known whether these additional upstream regulators function similarly in other models.…”