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The cap-to-tail guide to mRNA turnover

Key Points

  • Messenger RNA abundance is determined by balancing transcription and RNA decay. mRNA stability can be rapidly modulated to alter the expression of specific genes thereby providing flexibility in effecting changes in patterns of protein synthesis.

  • An evolutionarily conserved mRNA-degradation pathway is initiated by the removal of the 3′ poly(A) tail. This disrupts the translation initiation complex and provides degradative enzymes with access to the 5′ cap and remaining RNA body.

  • The intimate relationship between mRNA decay and translation is further indicated by the ability of translation-initiation factors and proteins that bind the poly(A) tail to protect the mRNA from degradation. Moreover, evidence shows that inhibiting translation elongation promotes mRNA stabilization

  • The turnover of mRNAs is also regulated by cis-acting elements that either promote or inhibit their decay. The most prevalent is the A+U-rich element (ARE), found in the 3′untranslated region (3′ UTR) of mRNAs encoding many important growth control proteins. ARE-binding proteins affect mRNA stability, translation and subcellular localization. Other elements found in the 5′ UTR and coding regions also modulate transcript stability.

  • Several signalling pathways are implicated in triggering changes in stability of specific mRNAs. One example is the interleukin-2 mRNA, which is stabilized by the c-Jun amino-terminal kinase (JNK) signalling pathway through JNK-responsive elements in its 5′UTR.

  • A strong link between translation and RNA turnover is also shown by nonsense-mediated decay, which ensures that mRNAs containing premature stop codons are degraded.

Abstract

The levels of cellular messenger RNA transcripts can be regulated by controlling the rate at which the mRNA decays. Because decay rates affect the expression of specific genes, they provide a cell with flexibility in effecting rapid change. Moreover, many clinically relevant mRNAs — including several encoding cytokines, growth factors and proto-oncogenes — are regulated by differential RNA stability. But what are the sequence elements and factors that control the half-lives of mRNAs?

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Figure 1: Deadenylation-dependent mRNA decay.
Figure 2: The deadenylase as an inhibitor of translation initiation and decapping.
Figure 3: Model for how the A+U-rich element mediates stability and instability.
Figure 4: Nonsense-mediated mRNA decay.

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DATABASE LINKS

Cystic fibrosis

Duchenne muscular dystrophy

Pab1

Pan2

Pan3

Ccr4

Caf1

Dcp1

Dcp2

Vps16

Pat1

PARN

PABP

eIF4G

eIF4E

Lsm1

AUF1

HuR

TIA-1

tristetraprolin

GM-CSF

NSAP1

Unr

IL-2

MEKK1

MKK6

Upf1

Upf2

Upf3

Hrp1

unc-54

smg-2

smg-7

smg-4

UPF1

UPF3

Y14

ALY

SRm160

RNPS1

DEK

FURTHER INFORMATION

Peltz home page

3′ UTR database

mRNA decay resource page

ENCYCLOPEDIA OF LIFE SCIENCES

mRNA stability

mRNA turnover

Glossary

CAP ANALOGUES

Dinucleotides such as 7-meGpppG or GpppG that resemble the 5′ cap structure of messenger RNAs. They can be used to analyse the specificity of cap-binding proteins or to compete them away from the 5′ cap structure.

3′ UNTRANSLATED REGION

Non-coding region that lies 3′ to the protein-coding part of a messenger RNA. Often contains sequences involved in RNA regulation.

5′ UNTRANSLATED REGION

Non-coding region that lies in front of (5′ to) the protein-coding part of a messenger RNA.

DOWNSTREAM SEQUENCE ELEMENT

A degenerate sequence element found in the coding region of most mRNAs, which can promote nonsense-mediated decay when located downstream of a premature stop codon.

HETEROLOGOUS NUCLEAR RIBONUCLEOPROTEIN

RNA-binding protein with a nuclear function. Many hnRNPs can shuttle between the nucleus and the cytoplasm, indicating that they might function in nuclear export of RNA.

MS2 COAT PROTEIN

A specific mRNA-binding protein from bacteriophage MS2 that recognizes a stem–loop structure. MS2 coat protein is often used to tether other proteins to RNAs.

POLYSOME

Polyribosome; two or more ribosomes attached to different points on the same strand of mRNA.

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Wilusz, C., Wormington, M. & Peltz, S. The cap-to-tail guide to mRNA turnover. Nat Rev Mol Cell Biol 2, 237–246 (2001). https://doi.org/10.1038/35067025

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