Concordant regulation of mRNA translation and 5’ to 3’ mRNA decay is
critical for precise control of gene expression. 5’ to 3’ mRNA decay initiates with
removal of the 3’ polyadenosine tail of mRNA (deadenylation). Deadenylation is
followed by removal of the 5’ 7‐methylguanosine cap (decapping) then 5’ to 3’
exonucleolytic degradation of the mRNA.
Historically, the decay field viewed decapping and degradation of mRNA as
occurring on ribosome‐free mRNAs. In brief, deadenylation occurred while mRNAs
were still loaded with ribosomes. Removal of the poly(A) tail was thought to allow
decapping activator proteins to inhibit translation initiation, which in turn led to run
off of ribosomes and ultimately ribosome‐free mRNA. Ribosome‐free mRNA was
then localized to distinct ribosome‐free subcellular sites termed processing bodies
(P‐bodies) for either storage or decapping and 5’ to 3’ degradation.
In this body of work, we highlight three major findings that fundamentally
altered this model. First, we discovered conditions that uncoupled the formation of
P‐bodies from changes in decay and translation, suggesting that P‐bodies are not
exclusive sites of bulk translational control and/or mRNA decay. Second, we show
that decapping and degradation of mRNAs can occur while they are still engaged
with polyribosomes, in stark contrast to the hypothesis that decay occurs in
ribosome‐free P‐bodies. Finally, we show that the decapping activator protein Dhh1
regulates a late step in translation in the context of polyribosomes rather than
inhibiting translation initiation and leading to ribosome‐free mRNA.
Based on these data, our model for the interface between translational
control and 5’ to 3’ mRNA decay explicitly allows for degradation of polyribosome
bound mRNAs rather than only ribosome‐free mRNAs. The new model also allows
for regulation of translation at steps later than initiation (i.e. – possibly elongation,
termination, or ribosome recycling), which would permit rapid translational
responses. Our revised model is more comprehensive as well as more reflective of
data from several organisms that indicate that translational control is not as simple
as regulation of translation initiation, nor is decay as simple as localization of
ribosome‐free mRNAs to P‐bodies.