Given the overall congruity of gene expression mecha-
nisms from yeast to humans, and the obvious need for
quality control, it comes as no surprise that the nonsense-
mediated mRNA decay (NMD) pathway is active in
all eukaryotes that have been examined, and that the
three core factors of this pathway are highly conserved.
However, these similarities notwithstanding, NMD in
higher eukaryotes seems to require several factors that are
not present in yeast and has been thought to incorporate
splicing-dependent mechanisms that are probably not
operative in organisms with few intron-containing genes.
Therefore, existing models for the respective mechanisms
of NMD in yeast and mammalian cells are not easily rec-
onciled. To address this problem, we propose a model
for NMD in yeast in which the underlying mechanism
that causes an mRNA to become an NMD substrate is
compatible with mRNA processing, translation and
degradative activities in all eukaryotes. Key elements of
this model address why some termination events, but not
others, can trigger NMD and consider functions for the
NMD factors in both translation termination and mRNA
decay, as well as the role of sequences that are located 3′
to the nonsense codon in promoting NMD.
An mRNA ‘life cycle’ and its untimely endings
Eukaryotic translation-competent mRNAs are typically
generated by a multi-step combination of transcription,
processing, nuclear export and messenger ribonucleo-
protein particle (mRNP) maturation. Once in the cyto-
plasm, translation of the mRNP ensues as it forms
a closed-loop structure that links the 5′ and 3′ ends of
the mRNA, associates with the requisite translation-
initiation factors, and binds to a 40S ribosomal subunit
that is itself replete with the initiator methionyl transfer RNA
and additional factors1–6 (FIG. 1). The recognition of the
initiator codon (generally, the AUG codon) and the sub-
sequent joining of a 60S ribosomal subunit complete the
initiation phase of protein synthesis and create an 80S
composite ribosome that decodes each nucleotide triplet
and elongates a fledgling polypeptide chain until a UAA,
UAG or UGA nonsense (or stop) codon is encountered.
For conventional mRNAs (that is, those with complete
open reading frames (ORFs)), nonsense-codon recogni-
tion promotes polypeptide hydrolysis, ribosome release
and, possibly, the recycling of the ribosome to the 5′ end
of the same mRNA7–11. These termination events (BOX 1)
are catalysed by two release factors, eRF1 and eRF3, and
are enhanced by the interaction of eRF3 with poly(A)-
binding protein (PABP), a highly conserved polypeptide
that associates with the 3′ poly(A) tail that is present on
almost all eukaryotic mRNAs12–18.
Termination can also occur prematurely; for example,
in transcripts that are derived from genes that harbour
nonsense mutations or in which errors in transcription or
processing have created a nonsense codon. In such tran-
scripts, the recognition of an ‘early’ nonsense codon not
only aborts protein synthesis, but also triggers the rapid
degradation of the mRNA by the NMD pathway19–21.
This quality-control system ensures that potentially toxic
polypeptide fragments do not accumulate22 while simul-
taneously coping with possible translational logjams that
might arise from the inherent inefficiency of premature
translation termination23.
Not all NMD substrates are defective transcripts
that are generated as a consequence of mutations or
synthesis errors. The NMD pathway also affects a large
number of endogenous substrates, including: inef-
ficiently spliced pre-mRNAs that enter the cytoplasm
with their introns intact, mRNAs in which the ribos-
ome has bypassed the initiator AUG and commenced
*Department of Molecular
Genetics and Microbiology,
University of Massachusetts
Medical School, Worcester,
Massachusetts 01655-0122,
USA.
‡Department of Environmental
and Biomolecular Systems,
Oregon Health and Science
University, Beaverton,
Oregon 97006, USA.
§Department of Molecular
Microbiology and
Immunology, Oregon Health
and Science University,
Portland, Oregon 97201,
USA.
Correspondence to A.J.
e-mail: allan.jacobson@
umassmed.edu
doi:10.1038/nrm1942
Nonsense codon
An alternative name for the
codons that do not designate
the insertion of a specific
amino acid during protein
synthesis in the standard
genetic code. Since UAA, UAG
and UGA also promote the
termination of protein
synthesis, these three codons
have also been termed ‘stop’
codons.
Messenger
ribonucleoprotein particle
An mRNA molecule and the
proteins that are bound to it.
Early nonsense: mRNA decay solves a
translational problem
Nadia Amrani*, Matthew S. Sachsठand Allan Jacobson*
Abstract | Gene expression is highly accurate and rarely generates defective proteins. Several
mechanisms ensure this fidelity, including specialized surveillance pathways that rid the cell
of mRNAs that are incompletely processed or that lack complete open reading frames. One
such mechanism, nonsense-mediated mRNA decay, is triggered when ribosomes encounter
a premature translation-termination — or nonsense — codon. New evidence indicates that
the specialized factors that are recruited for this process not only promote rapid mRNA
degradation, but are also required to resolve a poorly dissociable termination complex.
R E V I E W S
NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 7 | JUNE 2006 | 415