Aberrant mRNAs with extended 3′ UTRs are substrates for rapid degradation by mRNA surveillance

Abstract

The mRNA surveillance system is known to rapidly degrade aberrant mRNAs that contain premature termination codons in a process referred to as nonsense-mediated decay. A second class of aberrant mRNAs are those wherein the 3′ UTR is abnormally extended due to a mutation in the polyadenylation site. We provide several observations that these abnormally 3′-extended mRNAs are degraded by the same machinery that degrades mRNAs with premature nonsense codons. First, the decay of the 3′-extended mRNAs is dependent on the same decapping enzyme and 5′-to-3′ exonuclease. Second, the decay is also dependent on the proteins encoded by the UPF1, UPF2, and UPF3 genes, which are known to be specifically required for the rapid decay of mRNAs containing nonsense codons. Third, the ability of an extended 3′ UTR to trigger decay is prevented by stabilizing sequences within the PGK1 coding region that are known to protect mRNAs from the rapid decay induced by premature nonsense codons. These results indicate that the mRNA surveillance system plays a role in degrading abnormally extended 3′ UTRs. Based on these results, we propose a model in which the mRNA surveillance machinery degrades aberrant mRNAs due to the absence of the proper spatial arrangement of the translation-termination codon with respect to the 3′ UTR element as defined by the utilization of a polyadenylation site.