Looking at mRNA decay pathways through the window of molecular evolution

Culbertson, Michael R.; Leeds, Peter

doi:10.1016/s0959-437x(03)00014-5

Cited by 125 publications

(134 citation statements)

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“…[34][35][36][37][38] Thus, UPF1 is functionally the most important NMD factor and is the most evolutionarily conserved. 39,40 UPF1 also acts in non-NMD decay pathways, such as staufen1 (STAU1)-mediated mRNA decay (SMD) and replication-dependent histone mRNA decay. 41,42 Gene expression profiles of mammalian cells using siRNA-mediated depletion of UPF1 indicated that a significant fraction of cellular transcripts are upregulated, most of which are considered NMD-sensitive transcripts.…”

Section: Resultsmentioning

confidence: 99%

Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability

et al. 2012

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Section: Resultsmentioning

confidence: 99%

Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability

et al. 2012

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“…Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that detects and degrades mRNA containing premature termination codons (PTCs) to eliminate potentially harmful C-terminally truncated proteins (Peltz et al 1994;Wilkinson and Shyu 2001;Wilusz et al 2001;Culbertson and Leeds 2003;Baker and Parker 2004;Maquat 2004;Conti and Izaurralde 2005;Yamashita et al 2005). Aberrant proteins encoded by PTC-mRNA can have gain-of-function and dominantnegative effects that can result in genetic diseases (Frischmeyer and Dietz 1999;Holbrook et al 2004).…”

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confidence: 99%

“…All these genes are conserved in Drosophila melanogaster and mammals and have essential roles in NMD (Sun et al 1998;Yamashita et al 2001;Mendell et al 2002;Gatfield et al 2003;Ohnishi et al 2003;Kim et al 2005). The three components Upf1/ SMG-2, Upf2/SMG-3, and Upf3/SMG-4 are conserved in eukaryotes, and therefore, the three Upf/SMG proteins are core components of NMD (Culbertson and Leeds 2003). Upf1, an RNA helicase (Czaplinski et al 1995), interacts with Upf2, and Upf2, in turn, binds directly to Upf3 in S. cerevisiae (Weng et al 1996) and in mammals (Lykke-Andersen et al 2000;Mendell et al 2000;Serin et al 2001).…”

mentioning

confidence: 99%

“…In addition, Upf3b is part of the EJC and directly interacts with Y14, a core component of the EJC, in mammals (Kim et al 2001a;Le Hir et al 2001;LykkeAndersen et al 2001). Moreover, in S. cerevisiae, these three Upf proteins and eukaryotic release factors (eRF1 and eRF3) have been proposed to function as part of a "surveillance complex" that recognizes PTCs and triggers NMD (Peltz et al 1994;Culbertson and Leeds 2003), based on the genetic interactions of UPF genes for the recognition of translation termination codons and direct interactions between Upf proteins and eRF1 and eRF3 in vitro (Czaplinski et al 1998;Wang et al 2001) and in vivo (Kobayashi et al 2004). However, in mammals, the in vivo formation of the Upf protein and eRF1-eRF3 complex, as well as the mechanism of the interactions between the Upf/SMG proteins and EJC, remains to be clarified.…”

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confidence: 99%

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Binding of a novel SMG-1–Upf1–eRF1–eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay

Kashima¹,

Yamashita²,

Izumi³

et al. 2006

Genes Dev.

552

869

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Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that degrades mRNA containing premature termination codons (PTCs). In mammalian cells, recognition of PTCs requires translation and depends on the presence on the mRNA with the splicing-dependent exon junction complex (EJC). While it is known that a key event in the triggering of NMD is phosphorylation of the trans-acting factor, Upf1, by SMG-1, the relationship between Upf1 phosphorylation and PTC recognition remains undetermined. Here we show that SMG-1 binds to the mRNA-associated components of the EJC, Upf2, Upf3b, eIF4A3, Magoh, and Y14. Further, we describe a novel complex that contains the NMD factors SMG-1 and Upf1, and the translation termination release factors eRF1 and eRF3 (SURF). Importantly, an association between SURF and the EJC is required for SMG-1-mediated Upf1 phosphorylation and NMD. Thus, the SMG-1-mediated phosphorylation of Upf1 occurs on the association of SURF with EJC, which provides the link between the EJC and recognition of PTCs and triggers NMD.[Keywords: SMG-1; eRF; Upf; phosphorylation; EJC; NMD] Supplemental material is available at http://www.genesdev.org.

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“…NMD was first observed in Saccharomyces cerevisiae (40) and Caenorhabditis elegans (23) and seems to operate in all eukaryotes, including mammals (13). Recently, homologs of the three yeast NMD factors Upf1p, Upf2p, and Upf3p (for Up frameshift protein) have been identified in humans.…”

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confidence: 99%

hUPF2 Silencing Identifies Physiologic Substrates of Mammalian Nonsense-Mediated mRNA Decay

Wittmann

Hol

Jäck

2006

Molecular and Cellular Biology

216

213

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Nonsense-mediated mRNA decay (NMD) is a conserved eukaryotic surveillance pathway that selectively degrades aberrant mRNAs with premature termination codons (PTCs). Although a small number of cases exist in mammals, where NMD controls levels of physiologic PTC transcripts, it is still unclear whether the engagement of NMD in posttranscriptional control of gene expression is a more prevalent phenomenon. To identify physiologic NMD substrates and to study how NMD silencing affects the overall dynamics of a cell, we stably down-regulated hUPF2, the human homolog of the yeast NMD factor UPF2, by RNA interference. As expected, hUPF2-silenced HeLa cells were impaired in their ability to recognize ectopically expressed aberrant PTC transcripts. Surprisingly, hUPF2 silencing did not affect cell growth and viability but clearly diminished phosphorylation of hUPF1, suggesting a role of hUPF2 in modulating NMD activity through phosphorylation of hUPF1. Genome-wide DNA microarray expression profiling identified 37 novel up-regulated and 57 downregulated transcripts in hUPF2-silenced cells. About 60% of the up-regulated mRNAs carry typical NMD motifs. Hence, NMD is important not only for maintaining the transcriptome integrity by removing nonfunctional and aberrant PTC-bearing transcripts but also for posttranscriptional control of selected physiologic transcripts with NMD features.Eukaryotes have acquired numerous ways to control the integrity and quality of transcripts; one of them is the so-called nonsense-mediated mRNA decay (NMD). This posttranscriptional mRNA surveillance pathway recognizes and degrades aberrant (nonsense) transcripts with premature termination codons (PTCs), thereby preventing accumulation of truncated nonfunctional or potentially noxious polypeptides as well as dissipation of energy for translating aberrant mRNA. The physiological relevance of NMD is demonstrated in several pathological situations, where NMD-resistant nonsense mRNAs accumulate. For example, the presence of stable nonsense mRNAs encoding truncated ␤-globin or ␤-amyloid precursor protein correlates with the onset of ␤ 0 -thalassemia (52) or the formation of neuritic plaques in Alzheimer's patients (65), respectively.NMD was first observed in Saccharomyces cerevisiae (40) and Caenorhabditis elegans (23) and seems to operate in all eukaryotes, including mammals (13). Recently, homologs of the three yeast NMD factors Upf1p, Upf2p, and Upf3p (for Up frameshift protein) have been identified in humans. hUPF1/ rent1 (3,41,45,56,58), the human homolog of yeast UPF1/ regulator of nonsense transcripts, is an ATP-dependent RNA helicase (5), can be phosphorylated at serine residues in SQ motifs (55,70), and resides in the cytoplasm (3), although it can enter the nucleus (46). hUPF1 is supposed to trigger efficient degradation of nonsense transcripts once it has been recruited to the mRNA by hUPF2/rent2. hUPF2 can also be phosphorylated (12), has no known enzymatic activity, shows strong perinuclear staining, and interacts not only with hUPF1 (41) ...

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Looking at mRNA decay pathways through the window of molecular evolution

Cited by 125 publications

References 61 publications

Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability

Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability

Binding of a novel SMG-1–Upf1–eRF1–eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay

hUPF2 Silencing Identifies Physiologic Substrates of Mammalian Nonsense-Mediated mRNA Decay

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