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Mol. Cell. Biol. doi:10.1128/MCB.00272-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Regulation of H-ras Splice Variant Expression by a Cross-talk between the p53 and Nonsense-Mediated mRNA Decay Pathways

INSERM, U685, Equipe AVENIR, Hôpital Saint Louis, 1 Avenue Claude Vellefaux, Paris, F-75010, France

^* To whom correspondence should be addressed. Email: auboeuf{at}stlouis.inserm.fr.

	Abstract

When cells are exposed to a genotoxic stress, a DNA surveillance pathway that involves p53 is activated allowing DNA repair. Eukaryotic cells have also evolved a mechanism, called mRNA surveillance that controls the quality of mRNAs. Indeed, mutant mRNAs carrying premature translation termination codons (PTCs) are selectively degraded by the nonsense-mediated mRNA decay (NMD) pathway. However, in the case of particular genes, such as proto-oncogenes, mutations that do not create PTCs and therefore that do not induce mRNA degradation, can be harmful to cells. In this study, we showed that the H-ras gene in the absence of mutations produces an NMD-target splice variant that is degraded in the cytosol. We observed that a treatment with the genotoxic stress inducer camptothecin for 6 hours favoured the production of the H-ras NMD-target transcript degraded in the cytosol by the NMD process. Our data indicated that the NMD process allowed the elimination of transcripts produced in response to a short-term treatment with camptothecin from the major proto-oncogene H-ras, independently of PTCs induced by mutations. The camptothecin effects on H-ras gene expression were p53 dependent and involved in part the modulation of the SC35 splicing factor. Interestingly, a long-term treatment with camptothecin as well as p53 over-expression for 24 hours resulted in the accumulation of the H-ras NMD target in the cytosol, although the NMD process was not completely inhibited as other NMD targets are not stabilized. Finally, Upf1, a major NMD effector, was necessary for optimal p53 activation by camptothecin, which is consistent with recent data showing that NMD effectors are required for genome stability. In conclusion, we identified a cross-talk between the p53 and NMD pathways that regulates the expression levels of H-ras splice variants.