MARVELD1 Inhibits Nonsense-Mediated RNA Decay by Repressing Serine Phosphorylation of UPF1

Hu, Jianran; Li, Yu; Li, Ping

doi:10.1371/journal.pone.0068291

Cited by 10 publications

(11 citation statements)

References 31 publications

(53 reference statements)

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“…Moreover, MARVELD1 associated with potential NMD factor Importin β1, suggesting the possible function of MARVELD1 in NMD pathway 21 22 . Recent study in our lab further showed that MARVELD1 regulated NMD via modulating phosphorylation of UPF1 26 . Considering the aberrant regulation of MA RVELD1 gene in lung cancer, therefore, we discussed the gene silencing mechanism of MARVELD1 and the relationship between epigenetically masked MARVELD1 and NMD function in lung cancer cells.…”

Section: Discussionmentioning

confidence: 77%

Biological and clinical significance of epigenetic silencing of MARVELD1 gene in lung cancer

Shi

Wang

Yao

et al. 2014

Sci Rep

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Epigenetic silence in cancer frequently altered signal-transduction pathways during the early stages of tumor development. Recent progress in the field of cancer epigenetics has led to new opportunities for diagnosis and treatment of cancer. We previously demonstrated that novel identified nuclear factor MARVELD1 was widely expressed in human tissues, but down-regulated by promoter methylation in multiple cancers. This study was carried out to determine the biological and clinical significance of MARVELD1 gene silencing in lung cancer. Here, we found the reduced MARVELD1 expression significantly correlated with diagnostic histopathology and malignant degree of lung cancers. DNA hypermethylation and histone deacetylation synergistically inactivated MARVELD1 gene in lung cancer cells. Moreover, MARVELD1 modulated the efficiency of nonsense-mediated mRNA decay (NMD) through interaction with NMD core factor SMG1. The decreased MARVELD1 level in lung cancer reduces NMD efficiency through diminishing the association between NMD complex component UPF1/SMG1 and premature termination codons containing mRNA (PTC-mRNA). The results suggested that MARVELD1 silencing is an appealing diagnostic biomarker for lung cancer and epigenetic silencing of MARVELD1 gene links with the regulatory mechanism of NMD pathway in lung cancer, which may be required for tumorigenesis.

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Section: Discussionmentioning

confidence: 77%

Biological and clinical significance of epigenetic silencing of MARVELD1 gene in lung cancer

Shi

Wang

Yao

et al. 2014

Sci Rep

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“…In comparison, the stability of endogenous ORCL transcripts, which are not targeted by NMD, was unaffected under the same condition ( Fig. 3e ) 17 – 20 . It has been previously shown that the mRNA levels of many of the NMD factors such as SMG1, UPF1, UPF2, UPF3B, SMG5, SMG6 and SMG7 are controlled by NMD via an autoregulatory loop, as they are themselves targets of NMD 20 , 21 .…”

Section: Resultsmentioning

confidence: 92%

“…3e ) 17 – 20 . It has been previously shown that the mRNA levels of many of the NMD factors such as SMG1, UPF1, UPF2, UPF3B, SMG5, SMG6 and SMG7 are controlled by NMD via an autoregulatory loop, as they are themselves targets of NMD 20 , 21 . Consequently, these transcripts are upregulated upon ablation of NMD activity 21 , 22 .…”

Section: Resultsmentioning

confidence: 99%

Intracellular calcium regulates nonsense-mediated mRNA decay

Nickless

Jackson

Marasa

et al. 2014

Nat Med

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The nonsense-mediated mRNA decay (NMD) pathway selectively eliminates aberrant transcripts containing premature translation termination codons (PTCs) and regulates the levels of a number of physiological mRNAs. NMD modulates the clinical outcome of a variety of human diseases, including cancer and many genetic disorders, and may represent an important target for therapeutic intervention. Here we have developed a novel multicolored, bioluminescence-based reporter system that can specifically and effectively assay NMD in live human cells. Using this reporter system, we conducted a robust high-throughput small-molecule screen in human cells and, unpredictably, identified a group of cardiac glycosides including ouabain and digoxin as potent inhibitors of NMD. Cardiac glycoside-mediated effects on NMD are dependent on binding and inhibiting the Na+/K+-ATPase on the plasma membrane and subsequent elevation of intracellular calcium levels. Induction of calcium release from endoplasmic reticulum also leads to inhibition of NMD. Thus, this study reveals intracellular calcium as a key regulator of NMD and has important implications for exploiting NMD in the treatment of disease.

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“…Rassf1, Mat2a, Serpine1, and two Gadd45 paralogs are known or suspected substrates for either nonsense-mediated decay (NMD) or other pathways that recruit UPF1 (Forrest et al, 2004;Tani et al, 2012;Park and Maquat, 2013;Bresson et al, 2015;Nelson et al, 2016). Another outlier, the Marveld1 mRNA, has not yet been reported to interact with UPF1, but its protein product does interact with UPF1 in human cells and regulates UPF1 activity (Hu et al, 2013). Association with UPF1 can trigger endonucleolytic cleavage of mammalian mRNAs, which would decouple the rates of decay and deadenylation (Muhlemann and Lykke-Andersen, 2010), disrupting the relationship between half-life and tail length at intermediate labeling intervals.…”

Section: Correspondence Between Mrna Half-life and Deadenylation Ratementioning

confidence: 99%

The Dynamics of Cytoplasmic mRNA Metabolism

Eisen

Eichhorn

Subtelny

et al. 2019

Preprint

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For all but a few mRNAs, the dynamics of metabolism are unknown. Here, we developed an experimental and analytical framework for examining these dynamics for mRNAs from thousands of genes. mRNAs of mouse fibroblasts exit the nucleus with diverse intragenic and intergenic poly(A)-tail lengths. Once in the cytoplasm, they have a broad (1000-fold) range of deadenylation rate constants, which correspond to cytoplasmic lifetimes. Indeed, with few exceptions, degradation appears to occur primarily through deadenylation-linked mechanisms, with little contribution from either endonucleolytic cleavage or deadenylation-independent decapping. Most mRNA molecules degrade only after their tail lengths fall below 25 nt. Decay rate constants of short-tailed mRNAs vary broadly (1000-fold) and are more rapid for short-tailed mRNAs that had previously undergone more rapid deadenylation. This coupling helps clear rapidly deadenylated mRNAs, enabling the large range in deadenylation rate constants to impart a similarly large range in stabilities. Highlights:• mRNAs enter the cytoplasm with diverse intra-and intergenic lengths • mRNA deadenylation rates span a 1000-fold range and correspond to mRNA half-lives • After their tails become short, mRNAs decay at rates that span a 1000-fold range • More rapidly deadenylated mRNAs decay more rapidly upon reaching short tail lengths 3

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MARVELD1 Inhibits Nonsense-Mediated RNA Decay by Repressing Serine Phosphorylation of UPF1

Cited by 10 publications

References 31 publications

Biological and clinical significance of epigenetic silencing of MARVELD1 gene in lung cancer

Biological and clinical significance of epigenetic silencing of MARVELD1 gene in lung cancer

Intracellular calcium regulates nonsense-mediated mRNA decay

The Dynamics of Cytoplasmic mRNA Metabolism

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