The Double Life of UPF1 in RNA and DNA Stability Pathways

Azzalin, Claus M.; Lingner, Joachim

doi:10.4161/cc.5.14.3093

Cited by 51 publications

(56 citation statements)

References 21 publications

(39 reference statements)

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“…For instance, three smg genes, smg-2, smg-5, and smg-6, were shown to be required for persistence of RNAi in C. elegans, establishing a connection between mRNA surveillance and RNAi (Domeier et al 2000). In the case of SMG-2/UPF1, this essential NMD factor also has been shown to be required for genome stability, since its depletion induces cell cycle arrest early in S phase (Azzalin and Lingner 2006a; for review, see Azzalin and Lingner 2006b). Moreover, SMG-2/UPF1 is also involved in alternative mRNA degradation pathways, which are NMD-independent, by being recruited to 3ЈUTRs by the RNA-binding protein Staufen 1 (Kim et al 2005) or to the 3Ј end of histone mRNAs via the stem-loop-binding protein (Kaygun and Marzluff 2005).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway

Longman¹,

Plasterk²,

Johnstone³

et al. 2007

Genes Dev.

151

187

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The nonsense-mediated mRNA decay (NMD) pathway selectively degrades mRNAs harboring premature termination codons (PTCs). Seven genes (smg-1-7, for suppressor with morphological effect on genitalia) that are essential for NMD were originally identified in the nematode Caenorhabditis elegans, and orthologs of these genes have been found in several species. Whereas in humans NMD is linked to splicing, PTC definition occurs independently of exon boundaries in Drosophila. Here, we have conducted an analysis of the cis-acting sequences and trans-acting factors that are required for NMD in C. elegans. We show that a PTC codon is defined independently of introns in C. elegans and, consequently, components of the exon junction complex (EJC) are dispensable for NMD. We also show a distance-dependent effect, whereby PTCs that are closer to the 3 end of the mRNA are less sensitive to NMD. We also provide evidence for the existence of previously unidentified components of the NMD pathway that, unlike known smg genes, are essential for viability in C. elegans. A genome-wide RNA interference (RNAi) screen resulted in the identification of two such novel NMD genes, which are essential for proper embryonic development, and as such represent a new class of essential NMD genes in C. elegans that we have termed smgl (for smg lethal). We show that the encoded proteins are conserved throughout evolution and are required for NMD in C. elegans and also in human cells.[Keywords: Nonsense-mediated decay; smg genes; RNAi screens; exon junction complex; C. elegans] Supplemental material is available at http://www.genesdev.org. Nonsense-mediated mRNA decay (NMD) is a highly conserved surveillance mechanism present in all eukaryotes examined that prevents the synthesis of truncated proteins. It does so by promoting the degradation of mRNAs containing premature translation termination codons (PTCs) (for a recent review, see Maquat 2004). The functional importance of NMD is highlighted by the fact that this pathway targets for degradation a wide array of endogenous transcripts, as well as erroneously processed transcripts and transcripts carrying spontaneous mutations (for review, see Rehwinkel et al. 2006). It is proposed that NMD modulates the phenotypic outcome of many diseases, since ∼30% of inherited genetic disorders are caused by frameshift or nonsense mutations that generate premature termination codons (PTCs). Therefore, effectors of NMD are potential targets for therapeutic intervention (Frischmeyer and Dietz 1999;Holbrook et al. 2004).Genetic screens in the nematode Caenorhabditis elegans identified seven genes that are required for the degradation of nonsense mutant mRNAs of the unc-54 myosin heavy chain gene (Hodgkin et al. 1989;Pulak and Anderson 1993;Cali et al. 1999). In addition to their suppression-of-unc phenotype, these mutations cause abnormal morphogenesis of the male bursa and the hermaphrodite vulva, and accordingly these genes were termed smg-1-7 (for suppressor with morphological effect on genitalia). In the yeast Sac...

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Section: Discussionmentioning

confidence: 99%

Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway

Longman¹,

Plasterk²,

Johnstone³

et al. 2007

Genes Dev.

151

187

View full text Add to dashboard Cite

show abstract

“…In addition to its evolutionarily conserved function in NMD, accumulating evidence suggests that hSMG-1, as well as its downstream substrate, hUPf1, participate in various aspects of the DNA damage response (4,24,25). Indeed, the hSMG-1 kinase is activated by cellular exposure to ionizing radiation or UV light (4), and hUpf1 participates in both normal DNA replication and the cellular response to replication stress (24,26).…”

Section: Discussionmentioning

confidence: 99%

A Protective Role for the Human SMG-1 Kinase against Tumor Necrosis Factor-α-induced Apoptosis

Oliveira

Romanow

Geisen

et al. 2008

Journal of Biological Chemistry

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The human suppressor of morphogenesis in genitalia-1 (hSMG-1) protein kinase plays dual roles in mRNA surveillance and genotoxic stress response pathways in human cells. Here, we report that small interfering RNA-mediated depletion of hSMG-1, but not ATM, ATR, hUpf1, or hUpf2, in human U2OS osteosarcoma cells markedly increases the magnitude and accelerates the rate of apoptosis induced by tumor necrosis factor-␣ (TNF␣) stimulation. The increase in TNF␣-mediated cell killing observed in hSMG-1-depleted cells is not related to the suppression of nonsense-mediated mRNA decay or to the inhibition of TNF␣-induced NF-B activation. Rather, we observed that loss of hSMG-1 accelerates the degradation of the long form of the FLICE-inhibitory protein (FLIP L ), an inhibitor of death-inducing signaling complex-mediated caspase-8 activation, in TNF␣-treated cells. These results suggest that hSMG-1 plays an important role in cell survival during TNF␣-induced stress.

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“…Distinct specificities of human Ku interaction with hTR and hTERT have been reported (Chai et al, 2002;Ting et al, 2005), but the significance of these putative direct Kutelomerase interactions has not been tested in physiological context. The budding yeast telomerase protein Est1p binds to both the single-stranded telomeric repeat binding protein Cdc13p to telomerase RNP, but the human proteins hEST1A/hSMG6 and hEST1B/hSMG5 harboring limited similarity to Est1p have non-conserved roles in telomere biology (Lundblad, 2003;Azzalin and Lingner, 2006). Instead of using a mechanism similar to yeast telomerase, human telomerase recruitment to telomeres may be accomplished by interaction with the single-stranded telomeric repeat binding proteins TPP1 and POT1 (Wang et al, 2007;Xin et al, 2007).…”

Section: Regulation Of Telomere Elongationmentioning

confidence: 99%

Physiological assembly and activity of human telomerase complexes

Collins

2008

Mechanisms of Ageing and Development

104

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Telomerase is a specialized reverse transcriptase conserved throughout almost all eukaryotic life. It plays a fundamental role in genome maintenance, adding back the telomeric DNA repeats lost from chromosome ends due to incomplete replication or damage. The protein and RNA subunits of telomerase fold and function in a co-dependent manner to establish a high fidelity of telomeric repeat synthesis. Over the past two decades, studies of telomerase have uncovered previously unanticipated levels of complexity in its assembly, activity and regulation. This review describes the current understanding of telomerase in humans, with particular focus on telomerase biogenesis and regulation in its cellular context.

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The Double Life of UPF1 in RNA and DNA Stability Pathways

Cited by 51 publications

References 21 publications

Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway

Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway

A Protective Role for the Human SMG-1 Kinase against Tumor Necrosis Factor-α-induced Apoptosis

Physiological assembly and activity of human telomerase complexes

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