A novel function for alternative polyadenylation as a rescue pathway from NMD surveillance.

Premature termination codon (PTC) containing transcripts are subjected to a rapid degradation via nonsense-mediated decay (NMD) surveillance mechanism. By and large degradation is desired in order to prevent the translation of truncated, most likely deleterious, protein. Nevertheless, several dissimilar NMD-rescue events, capable of turning NMD-candidates into NMD-immune, are described. Yet, the extent and nature of this phenomenon is unknown. We screened the human genome for NMD-candidates transcripts. Among which we sub-grouped "pseudo-NMD" genes, which all their annotated transcripts contain PTCs, and therefore allegedly are transcribed but never translated. Here we show that alternative polyadenylation can rescue prematurely terminated transcripts, by truncating the pre-mRNA so that the PTC is now "legally" positioned. ESTs-based analysis shows that NMD-rescued genes are indeed expressed in human tissues. Furthermore, predicted NMD-rescue variants' existence is computationally verified. Hence, we suggest a novel role for the exon-truncated class of alternative polyadenylation as an NMD-rescue regulatory mechanism.

Under-representation of PolyA/PolyT tailed ESTs in human ESTdb: an obstacle to alternative polyadenylation inference.

Alternative polyadenylation is a key regulatory process which affects the 3' end formation of variants of the same transcription unit, thus altering gene expression pattern, and transcripts' cellular behaviour and characteristics. The common methodology for computational analysis of alternative polyadenylation signal utilization is based on EST data, specifically on PolyA/PolyT tailed ESTs. Studying the human ESTs dataset we detected a significant underrepresentation of PolyA/PolyT tailed ESTs, constituting only 10% of most libraries. Consequently, more than 50% of false-negative events are revealed in the analysis of alternatively polyadenylated variants' expression. We therefore argue that the ratios of PolyA/PolyT tailed ESTs, as represented in the human EST database, do not reflect the truepicture of 3' end variants formation of a given physiological situation. Thus the EST database should not be considered a reliable source for alternative polyadenylation signal usage inference.