Abstract
Proper regulation of mRNA production in the nucleus is critical for the maintenance of cellular homoeostasis during adaptation to internal and environmental cues. Over the past 25 years, it has become clear that the nuclear machineries governing gene transcription, pre-mRNA processing, pre-mRNA and mRNA decay, and mRNA export to the cytoplasm are inextricably linked to control the quality and quantity of mRNAs available for translation. More recently, an ever-expanding diversity of new mechanisms by which nuclear RNA decay factors finely tune the expression of protein-encoding genes have been uncovered. Here, we review the current understanding of how mammalian cells shape their protein-encoding potential by regulating the decay of pre-mRNAs and mRNAs in the nucleus.
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Acknowledgements
We thank E. Wagner and P. Boutz for the critical comments on the manuscript. X.R. was supported by an American Heart Association Career Development Award (854100) and National Institutes of Health (NIH) R21 AG075368. This work was additionally supported by NIH R37 GM74593 and NIH R01 GM059614 (now NIH R35 GM149268) to L.E.M.
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X.R. researched literature for the article. X.R. and L.E.M. contributed to the discussion of the content, wrote the manuscript, and edited and/or reviewed the manuscript before submission.
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Glossary
- Cajal bodies
-
Membraneless nuclear condensates, associated with the nucleolus, that have been implicated in the maturation of small nuclear ribonucleoproteins (snRNPs) and small nucleolar RNPs (snoRNPs), and telomerase assembly and trafficking.
- Cap-binding complex
-
(CBC). Heterodimer of cap-binding proteins CBP20 and CBP80 acquired co-transcriptionally during promoter-proximal pausing of RNAPII. The CBC positively influences gene transcription, pre-mRNA processing, nuclear mRNA export, pioneer round(s) of translation and nonsense-mediated decay.
- Cleavage and polyadenylation (CPA) complex
-
Modular multi-protein complex that recognizes polyadenylation signals and adjacent sequences in nascent RNAs to mediate their co-transcriptional cleavage and polyadenylation.
- Enhancer RNA
-
Short unstable non-coding nuclear RNA that cooperates with distant promoters to activate gene transcription by, for example, promoting chromatin looping and formation of RNA condensates.
- Exon–junction complexes
-
(EJCs). Heterogenous group of proteins deposited upstream of exon–exon junctions during pre-mRNA splicing that regulates multiple aspects of mRNA metabolism, including nuclear export, translation and nonsense-mediated decay.
- Integrator
-
Metazoan-specific modular multi-protein complex that terminates pervasive RNA polymerase II (RNAPII)-mediated transcription, RNAPII-mediated transcription at diverse functional non-coding transcriptional units, and RNAPII-mediated transcription during promoter-proximal pausing at protein-encoding genes.
- Nonsense-mediated mRNA decay
-
(NMD). Translation-dependent mRNA quality-control and quantity-control pathway that mediates the cytoplasmic decay of mRNAs terminating translation upstream of an exon–junction complex and/or a long or structured 3′-UTR.
- Non-stop mRNA decay
-
Decay pathway triggered when ribosomes translate to the 3′-end of an mRNA because the mRNA lacks a translation termination codon.
- Nuclear speckles
-
Membraneless nuclear organelles rich in transcription, pre-mRNA processing and nuclear export factors, small nuclear RNAs, and poly(A)+ RNAs. These structures are thought to function as storage centres and active sites of pre-mRNA processing.
- Paraspeckles
-
Membraneless nuclear organelles containing the long non-coding RNA NEAT1 and that influence nuclear RNA processes, such as by sequestering RNAs harbouring long double-stranded structures.
- Poly(A)-specific ribonuclease
-
(PARN). 5′-End cap-binding and poly(A)-binding protein best characterized for its ability to stabilize non-coding RNAs, including microRNAs and the telomerase RNA, via the removal of oligo(A) tails.
- Promoter-proximal pausing
-
RNAPII pausing ∼20–60 nucleotides downstream of a transcription start site. It constitutes a quality control checkpoint that regulates the transcription of most, if not all, protein-encoding genes in higher eukaryotes.
- Restrictor
-
ARS2-associated protein complex, composed of ZC3H4 and WDR82, that promotes transcription termination at non-coding genes or prematurely at protein-coding genes in a mechanism that probably does not require cleavage of the nascent RNA.
- Rixosome
-
Multienzyme complex that is formed by the RIX1 complex, which includes a SUMO protease activity, and a RNase polynucleotide kinase complex.
- RNAPII C-terminal domain
-
Tandem heptad repeats that extend the C-terminus of POLR2A, the largest RNAPII subunit, and whose complex phosphorylation status influences transcriptional and co-transcriptional processes.
- Serine–arginine-rich proteins
-
RNA-binding proteins with serine-rich and arginine-rich domains that couple gene transcription, pre-mRNA splicing and mRNA export to the cytoplasm.
- Transcription and export (TREX) complexes
-
A tetrameric assembly of four THO–UAP56 complexes recruited to spliced mRNA by ALYREF that licenses messenger ribonucleoproteins for nuclear export by NXF1–NXT1.
- Transposable elements
-
Repetitive DNA sequences, largely restricted to inactivated retrotransposon insertions, that constitute up to 50% of mammalian genomes. Although intragenic transposable elements can harbour regulatory functions, intergenic transposable elements are largely parasitic and silenced.
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Rambout, X., Maquat, L.E. Nuclear mRNA decay: regulatory networks that control gene expression. Nat Rev Genet (2024). https://doi.org/10.1038/s41576-024-00712-2
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DOI: https://doi.org/10.1038/s41576-024-00712-2