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NMD: a multifaceted response to premature translational termination
Stephanie Kervestin1 and Allan Jacobson2
Abstract | Although most mRNA molecules derived from protein-coding genes are destined to be translated into functional polypeptides, some are eliminated by cellular quality control pathways that collectively perform the task of mRNA surveillance. In the nonsense-mediated decay (NMD) pathway premature translation termination promotes the recruitment of a set of factors that destabilize a targeted mRNA. The same factors also seem to have key roles in repressing the translation of the mRNA, dissociating its terminating ribosome and messenger ribonucleoproteins (mRNPs), promoting the degradation of its truncated polypeptide product and possibly even feeding back to the site of transcription to interfere with splicingof the primary transcript.
Centre National de la Recherche Scientifique UPR9073, Universit Paris Diderot Sorbonne Paris Cit, Institut de Biologie Physicochimique, 13 rue Pierre et Marie Curie, 75005 Paris, France.
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655-00122, USA. Correspondence to A.J. e-mail: mailto:[email protected]
Web End =allan.jacobson@ mailto:[email protected]
Web End =umassmed.edu doi:10.1038/nrm3454 Published online 17 October 2012
Gene expression must maintain a high level of fidelity to ensure cell function and viability. To tackle this challenge, cells use multiple decay pathways to eliminate non-functional transcripts1,2. At the level of mRNA, three pathways operate during translation to protect the cell from the possible accumulation of aberrant mRNAs and potentially toxic proteins. These include: non-stop decay (NSD), which detects and degrades mRNAs lacking a stop codon35, no-go
decay (NGD), which targets mRNAs bound by ribosomes that are stalled in translation elongation68, and
nonsense-mediated decay (NMD), which promotes the degradation of mRNAs undergoing premature translation termination912. Although these pathways were originally thought to simply promote accelerated mRNA decay, recent studies suggest more complex post-transcriptiona l regulation13.
In NMD, UPF proteins, a set of conserved factors of which UPF1 is the central regulator, recruit decay enzymes to promote endo nucleolytic cleavage, 5 to 3 decay or 3 to 5 decay of prematurely terminating mRNAs. However, UPF proteins must also discriminate between normal and premature termination events and conduct ancillary processes that involve translational repression of mRNAs containing premature termination codons (PTCs), dissociate and properly recycle poorly dis sociable PTC-bound ribosomes and unwind the PTC-containing...