Control of gene expression through the nonsense-mediated RNA decay pathway

Nickless, Andrew; Bailis, Julie M.; You, Zhipeng

doi:10.1186/s13578-017-0153-7

Cited by 162 publications

(136 citation statements)

References 179 publications

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“…The precise regulation of genetic information, as it is passed from gene to transcript to protein, is crucial for the survival of cells and organisms. From a single gene, multiple mature messenger RNA (mRNA) transcripts arise through alternative pre-mRNA, resulting in mature species with differences in both the coding and non-coding regions [1]. Even beyond the end-points of mRNA transcription, the quality and quantity of mRNAs in cells is tightly controlled through various pathways [2].…”

Section: The Nonsense-mediated Mrna Decay (Nmd) Pathway and Machinerymentioning

confidence: 99%

“…However in humans, RNAi-based knockdowns on NMD genes showed that this pathway plays a crucial role in cell cycle regulation [48], cell viability [49] and the response to amino acid starvation [50]. Furthermore, NMD components have NMD-independent functions, such as the DNA damage response [51], maintenance of the telomere integrity [48], regulation of calcium metabolism [1], viral infection, replication [52] and tumourigenesis.…”

Section: Nmd In the Maintenance And Homeostasis Of The Cellmentioning

confidence: 99%

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Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

Pawlicka

Kalathiya

Alfaro

2020

Cancers

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Nonsense-mediated messenger RNA (mRNA) decay (NMD) is a surveillance pathway used by cells to control the quality mRNAs and to fine-tune transcript abundance. NMD plays an important role in cell cycle regulation, cell viability, DNA damage response, while also serving as a barrier to virus infection. Disturbance of this control mechanism caused by genetic mutations or dys-regulation of the NMD pathway can lead to pathologies, including neurological disorders, immune diseases and cancers. The role of NMD in cancer development is complex, acting as both a promoter and a barrier to tumour progression. Cancer cells can exploit NMD for the downregulation of key tumour suppressor genes, or tumours adjust NMD activity to adapt to an aggressive immune microenvironment. The latter case might provide an avenue for therapeutic intervention as NMD inhibition has been shown to lead to the production of neoantigens that stimulate an immune system attack on tumours. For this reason, understanding the biology and co-option pathways of NMD is important for the development of novel therapeutic agents. Inhibitors, whose design can make use of the many structures available for NMD study, will play a crucial role in characterizing and providing diverse therapeutic options for this pathway in cancer and other diseases.

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Section: The Nonsense-mediated Mrna Decay (Nmd) Pathway and Machinerymentioning

confidence: 99%

Section: Nmd In the Maintenance And Homeostasis Of The Cellmentioning

confidence: 99%

Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

Pawlicka

Kalathiya

Alfaro

2020

Cancers

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“…The increased skipping of exon 3 (out of 5) associated with the minor haplotype results in more transcripts with a frameshift and a premature termination codon (PTC) near the 5' end of exon 4. Many mammalian transcripts with PTCs are subject to nonsense-mediated decay (NMD), particularly when the PTC is not located in the last exon 67 . Treatment of cells with protein synthesis inhibitors such as cycloheximide (CHX) has been shown to increase the abundance of transcripts subject to NMD 68 .…”

Section: Fine Mapping Of Complex Ocular Disease Risk Locimentioning

confidence: 99%

Ocular disease mechanisms elucidated by genetics of human fetal retinal pigment epithelium gene expression

Liu

Calton

Benchorin

et al. 2018

Preprint

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The eye is an intricate organ with limited representation in large-scale functional genomics datasets. The retinal pigment epithelium (RPE) serves vital roles in ocular development and retinal homeostasis. We interrogated the genetics of gene expression of cultured human fetal RPE (fRPE) cells under two metabolic conditions. Genes with disproportionately high fRPE expression are enriched for genes related to inherited ocular diseases. Variants near these fRPE-selective genes explain a larger fraction of risk for both age-related macular degeneration (AMD) and myopia than variants near genes enriched in 53 other human tissues.Increased mitochondrial oxidation of glutamine by fRPE promoted expression of lipid synthesis genes implicated in AMD. Expression and splice quantitative trait loci (e/sQTL) analysis revealed shared and metabolic condition-specific loci of each type and several eQTL not previously described in any tissue. Fine mapping of fRPE e/sQTL across AMD and myopia genome-wide association data suggests new candidate genes, and mechanisms by which the same common variant of RDH5 contributes to both increased AMD risk and decreased myopia risk. Our study highlights the unique transcriptomic characteristics of fRPE and provides a resource to connect e/sQTL in a critical ocular cell type to monogenic and complex eye disorders.3The importance of vision to humans and the accessibility of the eye to examination have motivated the characterization of more than one thousand genetic conditions involving ocular phenotypes 1 . Among these, numerous monogenic diseases exhibit significant inter-and intra-familial phenotypic variability 2-7 . Imbalance in allelic expression of a handful of causative genes has been documented 8 , but common genetic variants responsible for such effects remain to be discovered.Complementing our knowledge of numerous monogenic ocular disorders, recent genome-wide association studies (GWAS) 9 have identified hundreds of independent loci associated with polygenic ocular phenotypes such as age-related macular degeneration (AMD), the leading cause of blindness in elderly individuals in developed countries 10,11 , and myopia, the most common type of refractive error worldwide and an increasingly common cause of blindness 12-14 . Despite the rapid success of GWAS in mapping novel ocular disease susceptibility loci, the functional mechanisms underlying these associations are often obscure.Connecting changes in molecular functions such as gene expression and splicing with specific GWAS genomic variants has aided the elucidation of functional mechanisms. Non-coding variants account for a preponderance of the most significant GWAS loci 15,16 , and most expression quantitative trait loci (eQTL) map to non-coding variants 17 . Thousands of eQTL have been found in a variety of human tissues 18 , but ocular celltypes are underrepresented among eQTL maps across diverse tissues, and no systematic search for eQTL has so far been described for any cell type in the human eye.The retinal pigment epithelium ...

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“…NMD was originally discovered through its role as a quality control mechanism that degrades aberrant mRNAs harboring premature termination codons generated by mutations, errors in splicing, and programmed gene rearrangements (Fig 1A;Nickless et al, 2017). Subsequently, NMD was found to also degrade subsets of normal mRNAs with stop codons in specific contexts.…”

mentioning

confidence: 99%

“…Increasing evidence suggests that the ability of NMD to degrade specific normal mRNAs is regulated and critical for a variety of functions ranging from differentiation and development to stress responses and autophagy. For example, NMD degrades the mRNA encoding the pro-apoptotic protein, GADD45, to allow for normal early fly development; NMD degrades Smad7 mRNA to promote selfrenewal of neural stem cells; and NMD degrades IRE1a mRNA to shape the unfolded protein stress response (Karam et al, 2013;Nickless et al, 2017).…”

mentioning

confidence: 99%

Nonsense shielding: protecting RNA from decay leads to cancer

Wilkinson

Cook-Andersen

2019

The EMBO Journal

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Despite intense scrutiny, the signals that determine whether a given RNA is degraded by the highly conserved and selective nonsense‐mediated RNA decay (NMD) pathway remain murky. In this issue of The EMBO Journal, Kishor et al shed light on this issue by demonstrating that the RNA‐binding protein, hnRNP L, protects a subset of RNAs from degradation by NMD. This mechanism is responsible for stabilizing the mRNA encoding the pro‐survival “oncogenic” protein, BCL‐2, in B‐cell lymphoma.

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Control of gene expression through the nonsense-mediated RNA decay pathway

Cited by 162 publications

References 179 publications

Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

Ocular disease mechanisms elucidated by genetics of human fetal retinal pigment epithelium gene expression

Nonsense shielding: protecting RNA from decay leads to cancer

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