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  • Review Article
  • Published:

The multiple lives of NMD factors: balancing roles in gene and genome regulation

Nature Reviews Genetics volume 9, pages 699–712 (2008)Cite this article

Key Points

  • Nonsense-mediated mRNA decay (NMD) largely provides a means to ensure the quality of gene expression by eliminating mRNAs that prematurely terminate translation either because of genomic mutations or errors in cellular processes.

  • NMD is also crucial to regulating proper expression levels for certain genes and for maintaining genome stability.

  • Up-frameshift (UPF) and phosphatidyl-inositol 3-kinase-related protein kinase (PIKK) SMG proteins are NMD factors, and incompletely defined combinations of these proteins demonstrate unexpected roles in pathways that have no apparent connection to NMD.

  • UPF1, which is an RNA-dependent ATPase and RNA helicase, functions in specialized pathways of mRNA decay, including Staufen 1 (STAU1)-mediated mRNA decay and the degradation of replication-dependent histone mRNAs at the end of the S phase of the cell cycle.

  • Apart from its role in histone mRNA decay, UPF1 influences DNA synthesis and cell-cycle progression by binding to chromatin in a way that is upregulated by the PIKKs ataxia-telangiectasia mutated and Rad 3-related (ATR), SMG1, and ataxia-telangiectasia mutated (ATM). Furthermore, UPF1 seems to be a component of DNA synthesis and repair pathways because it co-immunopurifies with DNA polymerase δ.

  • SMG1 has a role in stress-response pathways and DNA repair triggered by, for example, ionizing radiation, ultraviolet-B light or hyperoxia.

  • SMG and UPF factors function in the maintenance of telomeres at the ends of chromosomes by inhibiting the binding of telomeric repeat-containing RNA (TERRA) to telomeres.

  • In summary, SMG and UPF proteins can be viewed as components of overarching RNA and DNA surveillance processes and as multitasking players in the intricate network of signal transduction pathways that respond to genetic and acquired errors in nucleic-acid metabolism.

Abstract

Nonsense-mediated mRNA decay (NMD) largely functions to ensure the quality of gene expression. However, NMD is also crucial to regulating appropriate expression levels for certain genes and for maintaining genome stability. Furthermore, just as NMD serves cells in multiple ways, so do its constituent proteins. Recent studies have clarified that UPF and SMG proteins, which were originally discovered to function in NMD, also have roles in other pathways, including specialized pathways of mRNA decay, DNA synthesis and cell-cycle progression, and the maintenance of telomeres. These findings suggest a delicate balance of metabolic events — some not obviously related to NMD — that can be influenced by the cellular abundance, location and activity of NMD factors and their binding partners.

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Figure 1: Models for nonsense-mediated mRNA decay in Saccharomyces cerevisiae and mammals.
Figure 2: UPF1 function in specialized mRNA-decay pathways.
Figure 3: Phosphorylated UPF1 functions when DNA is damaged or replication is otherwise blocked.
Figure 4: UPF1 and SMG1 are at the interface of processes important for gene and genome regulation in mammalian cells.

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Acknowledgements

We thank C. Woeller for reading the manuscript and help with its formatting and G. Chanfreau for conversations. The Maquat lab is supported by NIH R01 grants GM074593 and GM059514 to L.E.M.

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Authors and Affiliations

  1. Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, BOX 712, Rochester, 14642, New York, USA

    Olaf Isken & Lynne E. Maquat

  2. Currently at the Department of Medical Molecular Biology, University of Lübeck, Ratzeburger Allee 160, 23438 Lübeck, Germany.,

    Olaf Isken

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Glossary

Telomeres

Condensed repetitive DNA sequences at chromosomal ends in most eukaryotes that compensate for incomplete semi-conservative DNA replication by protecting against homologous recombination and non-homologous end joining, thereby conferring genomic stability.

Oxidative stress

A disturbance in the normal redox state of a cell that is due to an imbalance between the production of reactive oxygen and either detoxification of the resulting reactive intermediates (for example, peroxides and free radicals) or repair of the consequential damage. Oxidative-stress damage can potentially occur to all components of the cell, including proteins, lipids and DNA.

Phosphatidylinositol 3-kinase-related protein kinase

(PIKK). Examples include ATM, ATR, SMG1, DNA-PK and mTOR. PIKKs constitute a subfamily of serine and threonine kinases that resemble lipid kinase phosphatidylinositol 3-kinases (PI-3 kinases). PIKKs transduce signals in cell-growth and stress-response pathways.

Histone

Protein component of chromatin that functions to regulate gene expression and is synthesized coordinately with DNA replication. Two each of the core histones H2A, H2B, H3 and H4 make up an octameric nucleosome, around which DNA winds. The linker histone H1 binds the nucleosome, locking the DNA into place.

Premature termination codon

(PTC). UAA, UGA or UAG codon (that is, a nonsense codon, which generally does not encode an amino acid) within mRNA. PTCs are situated upstream of the normal termination codon and direct the premature termination of mRNA translation, which usually results in nonsense-mediated mRNA decay.

Exon-junction complex

(EJC). Complex of proteins that is deposited ∼20–25 nucleotides upstream of the exon–exon junctions of newly synthesized spliced mRNAs. Despite its potentially ancient origin, the EJC functions in mammalian-cell and plant-cell NMD but not detectably in NMD in other organisms studied.

RNA cap-binding protein

(CBP). Protein that binds the 7-methyl guanosine cap structure at the 5′ end of mRNAs. In mammalian cells, mRNA is bound first by the mostly nuclear but shuttling CBP heterodimer CBP80–CBP20. Subsequently, CBP80–CBP20 is replaced by eukaryotic translation initiation factor 4E (eIF4E), a state that typifies the bulk of cellular mRNA.

NMD degradative activities

Decapping and 5′-to-3′ exonucleolytic activities as well as deadenylating and 3′-to-5′ exosome-mediated activities.

Selenoprotein mRNA

One of a number of mRNAs, exemplified by glutathione peroxidase 1 mRNA, that harbour one or more UGA codons that direct the incorporation of the twenty-first amino acid, selenocysteine. Incorporation, which competes with translation termination, requires at least one cis-acting selenocysteine insertion element that resides in the mRNA 3′ UTR.

Serine–arginine (SR)-rich protein

Member of an evolutionarily conserved family of essential pre-mRNA splicing factors in metazoans. Individual SR proteins have distinct but occasionally overlapping abilities to promote 5′ splice-site usage. They also function in post-transcriptional steps that occur after pre-mRNA splicing.

Heterogeneous nuclear ribonucleoprotein (hnRNP) splicing factor

hnRNP proteins that, in metazoans, can either repress or enhance splicing by antagonizing or promoting splice-site selection. Cooperative interactions between pre-mRNA-bound hnRNP proteins might enhance splicing between specific pairs of splice sites while at the same time inhibiting other combinations of splice-site usage.

Alternative splicing

Used to generate the multiple mRNAs that derive from at least 75% of human genes, often in a tissue-specific manner, as a means to generate more than one protein isoform per gene. An estimated one-third of alternatively spliced human mRNAs are targeted for NMD.

Pre-mRNA splicing

Nuclear process whereby one or more introns, or intervening sequences, are removed from a primary gene transcript, or a pre-mRNA, and the resulting exons are coordinately ligated together to form mRNA.

Upstream ORF

An open translational reading frame that exists upstream of a protein-encoding reading frame. Upstream ORFs are usually short and are often regulatory, lacking the potential to encode a functional protein. Translation termination at an upstream ORF can result in NMD.

Telomerase

A reverse transcriptase that uses its constituent RNA as a template to add specific DNA repeats — TTAGGG in all vertebrates — to the 3′-extended ends of telomeres, which are shortened after each replication cycle.

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Isken, O., Maquat, L. The multiple lives of NMD factors: balancing roles in gene and genome regulation. Nat Rev Genet 9, 699–712 (2008). https://doi.org/10.1038/nrg2402

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