NAM7 nuclear gene encodes a novel member of a family of helicases with a Zn-ligand motif and is involved in mitochondrial functions in Saccharomyces cerevisiae

Altamura, Nicola; Groudinsky, Olga; Dujardin, Geneviève; Słonimski, Piotr P.

doi:10.1016/0022-2836(92)90545-u

Cited by 88 publications

(78 citation statements)

References 48 publications

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“…However, residual amounts of hUPF2 could be sufficient for viability, and perhaps a complete hUPF2 knockout would have a more severe phenotype. On the one hand, this was not surprising since the deletion of any of the hUPF orthologs in yeast and C. elegans had only a minor effect on overall growth and development (1,23). In contrast, homozygous deletion of mUPF1/rent1 in the mouse genome leads to an embryonic lethal phenotype at a very early stage and to apoptosis of cultured mUPF1/rent1 Ϫ/Ϫ blastocysts (44).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The UPF1 gene has been cloned and sequenced and shown to be (1) nonessential for viability, (2) capable of encoding a 109-kD protein with both zinc finger, nucleotide (GTP)-binding site and RNA helicase motifs, (3) identical to NAM7, a nuclear gene that was isolated as a high-copy suppressor of mitochondrial RNA splicing mutations, and (4) partially homologous to the yeast SEN1 gene (Leeds et al 1991(Leeds et al ,1992Altamura et al 1992;Koonin 1992). The latter encodes a noncatalytic subunit of the tRNA splicing endonuclease complex (Winey and Culbertson 1988), suggesting that Upflp may also be part of a nuclease complex targeted specifically to nonsensecontaining mRNAs.…”

Section: Nonsense-mediated Mrna Decay Requires the Activity Of The Upmentioning

confidence: 99%

mRNA destabilization triggered by premature translational termination depends on at least three cis-acting sequence elements and one trans-acting factor.

Peltz¹,

Brown²,

Jacobson³

1993

Genes Dev.

286

349

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Nonsense mutations in a gene can accelerate the decay rate of the mRNA transcribed from that gene, a phenomenon we describe as nonsense-mediated mRNA decay. Using amber (UAG) mutants of the yeast PGK1 gene as a model system, we find that nonsense-mediated mRNA decay is position dependent, that is, nonsense mutations within the initial two-thirds of the PGKl-coding region accelerate the decay rate of the PGK1 transcript ~<12-fold, whereas nonsense mutations within the carboxy-terminal third of the coding region have no effect on mRNA decay. Moreover, we find that this position effect reflects (1) a requirement for sequences 3' to the nonsense mutation that may be necessary for translational reinitiation or pausing, and (2) the presence of an additional sequence that, when translated, inactivates the nonsense-mediated mRNA decay pathway. This stabilizing element is positioned within the coding region such that it constitutes the boundary between nonsense mutations that do or do not affect mRNA decay. Rapid decay of PGK1 nonsense-containing transcripts is also dependent on the status of the UPF1 gene. Regardless of the position of an amber codon in the PGK1 gene, deletion of the UPF1 gene restores wild-type decay rates to nonsense-containing PGK1 transcripts.

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“…Human orthologs of each of these proteins have been identified, termed Rent1-3/hUpf1-3 (11)(12)(13)(14)(15). Complete loss of NMD in lower eukaryotes is well tolerated (16)(17)(18)(19). However, homozygous targeted disruption of Rent1/Upf1 in mice resulted in stabilization of nonsense transcripts to WT levels and death at the periimplantation stage of development (20).…”

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confidence: 99%

Perturbation of thymocyte development in nonsense-mediated decay (NMD)-deficient mice

Frischmeyer‐Guerrerio¹,

Montgomery²,

Warren³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The random nature of T-cell receptor-β (TCR-β) recombination needed to generate immunological diversity dictates that two-thirds of alleles will be out-of-frame. Transcripts derived from nonproductive rearrangements are cleared by the nonsense-mediated mRNA decay (NMD) pathway, the process by which cells selectively degrade transcripts harboring premature termination codons. Here, we demonstrate that the fetal thymus in transgenic mice that ubiquitously express a dominant-negative form of Rent1/hUpf1, an essential trans -effector of NMD, shows decreased cell number, reduced CD4CD8 double-positive thymocytes, diminished expression of TCR-β, and increased expression of CD25, suggesting a defect in pre-TCR signaling. Transgenic fetal thymocytes also demonstrated diminished endogenous Vβ-to-DβJβ rearrangements, whereas Dβ-to-Jβ rearrangements were unperturbed, suggesting that inhibition of NMD induces premature shut-off of TCR-β rearrangement. Developmental arrest of thymocytes is prevented by the introduction of a fully rearranged TCR-β transgene that precludes generation of out-of-frame transcripts, suggesting direct mRNA-mediated trans -dominant effects. These data document that NMD has been functionally incorporated into developmental programs during eukaryotic evolution.

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NAM7 nuclear gene encodes a novel member of a family of helicases with a Zn-ligand motif and is involved in mitochondrial functions in Saccharomyces cerevisiae

Cited by 88 publications

References 48 publications

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

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

mRNA destabilization triggered by premature translational termination depends on at least three cis-acting sequence elements and one trans-acting factor.

Perturbation of thymocyte development in nonsense-mediated decay (NMD)-deficient mice

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