Trends in Genetics
Bringing the role of mRNA decay in the control of gene expression into focus
Section snippets
An assortment of mRNA decay enzymes
The enzymes involved in mRNA decay are described in Table 1; because they were recently the subject of a detailed review [11] only a brief overview will be given here. Studies from both yeast (Saccharomyces cerevisiae) and mammalian systems indicate that the majority of normal mRNAs decay by a deadenylation-dependent pathway that initiates with removal of the poly(A) tail (Figure 1). Several poly(A)-specific exoribonucleases have been identified in yeast and higher eukaryotes 12, 13, 14.
Regulation of mRNA decay pathways
It is important to emphasize that mRNA turnover is a highly regulated process. Each step of the pathway is subject to control either globally or, more often, in a sequence-specific manner. Potential avenues for modulation include altering the expression, activity or localization of the enzymes themselves, recruitment or inhibition of the decay enzymes by proteins associated with specific mRNA sequences, and altering expression, activity or localization of RNA-binding factors. Some examples are
Regulation of mRNA-binding proteins
Although a wide variety of factors that interact with mRNA stability elements have been identified, the mechanism of action is known for only a few. Nevertheless, most proteins that bind such regulatory sequences have been designated as having a stabilizing or destabilizing influence. Importantly, the array of proteins bound to a stability element can be drastically altered in response to cellular signals. Such signals can lead to post-translational modification of RNA-binding factors, or their
Synchronizing mRNA decay rates
As can be seen, mRNA turnover is a complex process requiring multiple enzymes and factors, and can be controlled at many points. Therefore, regulation of mRNA decay can be very specific, affecting only one or two mRNAs containing a particular sequence element under certain stimuli, or more widespread, by altering the decay of a group of transcripts with related functions.
It has been suggested that control of mRNA decay is utilized by the cell to coordinate expression of genes involved in
Coordinated control of gene expression at multiple levels
Importantly, regulation of mRNA turnover is not isolated from modulation at other steps such as transcription, processing, export and translation of mRNAs. There are highly complex networks of interacting pathways that enable rapid, coordinated and dramatic responses to cellular stimuli, and some examples are given below.
One way the cell accomplishes flexible control over a large number of genes is through regulating the stability of mRNAs encoding transcription factors. The Schizosaccharomyces
What next?
It should now be clear that mRNA decay pathways make a huge contribution to the global control of gene expression and to regulating expression of specific genes in response to signals. However, the mechanisms by which regulation is achieved remain obscure in many cases. One enduring question is how is deadenylation initiated? Is PABP dissociated transiently during translation or must it be forcibly removed to allow deadenylation to occur? Can some RNA-binding proteins enhance the rate of
Acknowledgements
C.J.W. is supported by the American Heart Association Award #0130470T. J.W. is supported by grants from the National Institutes of Health. We are grateful to members of the Wilusz Laboratory and to Shobha Vasudevan for critical reading of the manuscript.
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