Contribution of copy number variants involving nonsense-mediated mRNA decay pathway genes to neuro-developmental disorders

Nguyen, Lam Son; Kim, Hyung‐Goo; Rosenfeld, Jill A.; Shen, Yiping; Gusella, James F.; Lacassie, Yves; Layman, Lawrence C.; Shaffer, Lisa G.; Gécz, Jozef

doi:10.1093/hmg/ddt035

Cited by 130 publications

(134 citation statements)

References 66 publications

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“…In humans, two UPF3 paralogs, UPF3 and UPF3X (also called UPF3A and UPF3B, respectively), differently modulate NMD activity (Chan et al, 2009;Kunz et al, 2006;Lykke-Andersen et al, 2000;Serin et al, 2001) in ways that, like UPF1 and another NMD factor, UPF2, have been shown to be crucial for, for example, normal neuronal maturation and development (Colak et al, 2013;Jolly et al, 2013;Laumonnier et al, 2010;Lou et al, 2014;Nguyen et al, 2012Nguyen et al, , 2013Tarpey et al, 2007). UPF3 or UPF3X are generally associated with exon junction complexes (EJCs; see below) that are deposited in the nucleus upstream of newly spliced exon-exon junctions, whereas UPF2 is generally associated with EJCs after newly synthesized mRNAs are exported to the cytoplasm (Kim et al, 2001;Lejeune et al, 2002;Lykke-Andersen et al, 2001).…”

Section: Central Nmd Factors In Human Cellsmentioning

confidence: 99%

Nonsense-mediated mRNA decay in humans at a glance

Kurosaki

Maquat

2016

Journal of Cell Science

295

290

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Nonsense-mediated mRNA decay (NMD) is an mRNA quality-control mechanism that typifies all eukaryotes examined to date. NMD surveys newly synthesized mRNAs and degrades those that harbor a premature termination codon (PTC), thereby preventing the production of truncated proteins that could result in disease in humans. This is evident from dominantly inherited diseases that are due to PTC-containing mRNAs that escape NMD. Although many cellular NMD targets derive from mistakes made during, for example, pre-mRNA splicing and, possibly, transcription initiation, NMD also targets ∼10% of normal physiological mRNAs so as to promote an appropriate cellular response to changing environmental milieus, including those that induce apoptosis, maturation or differentiation. Over the past ∼35 years, a central goal in the NMD field has been to understand how cells discriminate mRNAs that are targeted by NMD from those that are not. In this Cell Science at a Glance and the accompanying poster, we review progress made towards this goal, focusing on human studies and the role of the key NMD factor upframeshift protein 1 (UPF1).

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Section: Central Nmd Factors In Human Cellsmentioning

confidence: 99%

Nonsense-mediated mRNA decay in humans at a glance

Kurosaki

Maquat

2016

Journal of Cell Science

295

290

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“…The idea that misregulation of NMD predisposes for neurodevelopmental disorders is supported by an association with heterozygous deletions of a genomic region that include UPF2 [197]. In addition, a de novo missense mutation in UPF2 has been identified in a patient with schizophrenia [198].…”

Section: Upf2mentioning

confidence: 99%

Mechanism, factors, and physiological role of nonsense-mediated mRNA decay

Fatscher

Boehm

Gehring

2015

Cell. Mol. Life Sci.

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Nonsense-mediated mRNA decay (NMD) is a translation-dependent, multistep process that degrades irregular or faulty messenger RNAs (mRNAs). NMD mainly targets mRNAs with a truncated open reading frame (ORF) due to premature termination codons (PTCs). In addition, NMD also regulates the expression of different types of endogenous mRNA substrates. A multitude of factors are involved in the tight regulation of the NMD mechanism. In this review, we focus on the molecular mechanism of mammalian NMD. Based on the published data, we discuss the involvement of translation termination in NMD initiation. Furthermore, we provide a detailed overview of the core NMD machinery, as well as several peripheral NMD factors, and discuss their function. Finally, we present an overview of diseases associated with NMD factor mutations and summarize the current state of treatment for genetic disorders caused by nonsense mutations.

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“…NMD also degrades ;5%-10% of naturally occurring mRNAs, often as a means of maintaining cellular homeostasis (Huang and Wilkinson 2012;Schweingruber et al 2013) or regulating developmental processes that include axon guidance, synaptic strength, and neuronal expression (Giorgi et al 2007;Colak et al 2013). These functions explain at least in part the intellectual disabilities that typify NMD factor deficiencies (Nguyen et al 2012(Nguyen et al , 2013.…”

mentioning

confidence: 99%

A post-translational regulatory switch on UPF1 controls targeted mRNA degradation

et al. 2014

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Nonsense-mediated mRNA decay (NMD) controls the quality of eukaryotic gene expression and also degrades physiologic mRNAs. How NMD targets are identified is incompletely understood. A central NMD factor is the ATP-dependent RNA helicase upframeshift 1 (UPF1). Neither the distance in space between the termination codon and the poly(A) tail nor the binding of steady-state, largely hypophosphorylated UPF1 is a discriminating marker of cellular NMD targets, unlike for premature termination codon (PTC)-containing reporter mRNAs when compared with their PTC-free counterparts. Here, we map phosphorylated UPF1 (p-UPF1)-binding sites using transcriptomewide footprinting or DNA oligonucleotide-directed mRNA cleavage to report that p-UPF1 provides the first reliable cellular NMD target marker. p-UPF1 is enriched on NMD target 39 untranslated regions (UTRs) along with suppressor with morphogenic effect on genitalia 5 (SMG5) and SMG7 but not SMG1 or SMG6. Immunoprecipitations of UPF1 variants deficient in various aspects of the NMD process in parallel with F€ orster resonance energy transfer (FRET) experiments reveal that ATPase/helicase-deficient UPF1 manifests high levels of RNA binding and disregulated hyperphosphorylation, whereas wild-type UPF1 releases from nonspecific RNA interactions in an ATP hydrolysis-dependent mechanism until an NMD target is identified. 39 UTR-associated UPF1 undergoes regulated phosphorylation on NMD targets, providing a binding platform for mRNA degradative activities. p-UPF1 binding to NMD target 39 UTRs is stabilized by SMG5 and SMG7. Our results help to explain why steady-state UPF1 binding is not a marker for cellular NMD substrates and how this binding is transformed to induce mRNA decay.

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Contribution of copy number variants involving nonsense-mediated mRNA decay pathway genes to neuro-developmental disorders

Cited by 130 publications

References 66 publications

Nonsense-mediated mRNA decay in humans at a glance

Nonsense-mediated mRNA decay in humans at a glance

Mechanism, factors, and physiological role of nonsense-mediated mRNA decay

A post-translational regulatory switch on UPF1 controls targeted mRNA degradation

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