In a prior proof-of-principle experiment, we utilized the well characterized À1 PRF signal from the yeast L-A dsRNA virus to demonstrate that these elements can generally function as mRNA destabilizing elements through the NMD pathway (19) . Subsequently, a bioinformatics approach was used to determine that potential À1 RF signals are widely found in all genomes examined, and that the great majority of these are predicted to direct elongating ribosomes to premature termination codons (15, 17) . Here, we show that these chromosomally encoded, endogenous À1 RF signals can also function as cis-acting mRNA destabilizing elements, both in the context of a reporter mRNA, and also in one case in a natural context. Further, we demonstrated that À1 RF signals can differentially affect mRNA abundance through the NMD pathway, and the data are also consistent with destabilization through NGD. These are modeled in Figure 5 . In support of this idea, the EST2, BUB3 and SPR6 mRNAs were all stabilized in upf1D, upd2D/nmd2D, upf3D, dcp1D and xrn1D cells (37) , and the half-lives of these mRNAs were less than the mean in wild-type cells (38) . Interestingly, TBF1 is not represented in these databases. In the case of a ribosome shifting reading frame into a PTC, the surveillance complex led by the Upf proteins signals rapid decapping by Dcp1p/Dcp2p, followed by deadenylation and exonucleolytic decay via Xrn1p and the exosome. In parallel, the NGD pathway can be activated by ribosomes that are stalled at strong secondary structures in mRNAs. Stalled ribosomes are freed from mRNAs by Dom34p/Hbs1p, promoting exonucleolytic cleavage at unpaired nucleotides near the pause, thus resulting in two mRNA fragments which become substrates for decapping and exonucleolytic decay [reviewed in (39) ]. The findings presented here suggest that cells are not only well equipped to deal with aberrant messages which contain premature termination codons and to clear stalled ribosomes from mRNAs, but have also evolved to capitalize upon these functions to post-transcriptionally regulate gene expression.