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

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2020 Mar 28

PMID 32213869

Citations 25

Authors

Kamila Pawlicka

Umesh Kalathiya

Javier Alfaro

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Nonsense-Mediated mRNA Decay in Human Health and Diseases: Current Understanding, Regulatory Mechanisms and Future Perspectives.

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The Many Roads from Alternative Splicing to Cancer: Molecular Mechanisms Involving Driver Genes.

Gimeno-Valiente F, Lopez-Rodas G, Castillo J, Franco L Cancers (Basel). 2024; 16(11).

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A Novel Four-Gene Signature Based on Nonsense-Mediated RNA Decay for Predicting Prognosis in Hepatocellular Carcinoma: Bioinformatics Analysis and Functional Validation.

Zhao J, Wang C, Zhao L, Zhou H, Wu R, Zhang T J Hepatocell Carcinoma. 2024; 11:747-766.

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Readthrough Activators and Nonsense-Mediated mRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons.

Benslimane N, Loret C, Chazelas P, Favreau F, Faye P, Lejeune F Pharmaceuticals (Basel). 2024; 17(3).

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In Vitro Cross-Linking MS Reveals SMG1-UPF2-SMG7 Assembly as Molecular Partners within the NMD Surveillance.

Padariya M, Vojtesek B, Hupp T, Kalathiya U Int J Mol Sci. 2024; 25(6).

PMID: 38542156 PMC: 10969982. DOI: 10.3390/ijms25063182.

References

Karam R, Carvalho J, Bruno I, Graziadio C, Senz J, Huntsman D . The NMD mRNA surveillance pathway downregulates aberrant E-cadherin transcripts in gastric cancer cells and in CDH1 mutation carriers. Oncogene. 2008; 27(30):4255-60. DOI: 10.1038/onc.2008.62. View

Celik A, Kervestin S, Jacobson A . NMD: At the crossroads between translation termination and ribosome recycling. Biochimie. 2014; 114:2-9. PMC: 4430455. DOI: 10.1016/j.biochi.2014.10.027. View

Gehring N, Neu-Yilik G, Schell T, Hentze M, Kulozik A . Y14 and hUpf3b form an NMD-activating complex. Mol Cell. 2003; 11(4):939-49. DOI: 10.1016/s1097-2765(03)00142-4. View

Fukuhara N, Ebert J, Unterholzner L, Lindner D, Izaurralde E, Conti E . SMG7 is a 14-3-3-like adaptor in the nonsense-mediated mRNA decay pathway. Mol Cell. 2005; 17(4):537-47. DOI: 10.1016/j.molcel.2005.01.010. View

Smith J, Baker K . Nonsense-mediated RNA decay--a switch and dial for regulating gene expression. Bioessays. 2015; 37(6):612-23. PMC: 4454373. DOI: 10.1002/bies.201500007. View

Balistreri G, Horvath P, Schweingruber C, Zund D, McInerney G, Merits A . The host nonsense-mediated mRNA decay pathway restricts Mammalian RNA virus replication. Cell Host Microbe. 2014; 16(3):403-11. DOI: 10.1016/j.chom.2014.08.007. View

Alrahbeni T, Sartor F, Anderson J, Miedzybrodzka Z, McCaig C, Muller B . Full UPF3B function is critical for neuronal differentiation of neural stem cells. Mol Brain. 2015; 8:33. PMC: 4445987. DOI: 10.1186/s13041-015-0122-1. View

Kurosaki T, Maquat L . Nonsense-mediated mRNA decay in humans at a glance. J Cell Sci. 2016; 129(3):461-7. PMC: 4760306. DOI: 10.1242/jcs.181008. View

Lykke-Andersen S, Chen Y, Ardal B, Lilje B, Waage J, Sandelin A . Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes. Genes Dev. 2014; 28(22):2498-517. PMC: 4233243. DOI: 10.1101/gad.246538.114. View

10.

Cheng Z, Saito K, Pisarev A, Wada M, Pisareva V, Pestova T . Structural insights into eRF3 and stop codon recognition by eRF1. Genes Dev. 2009; 23(9):1106-18. PMC: 2682955. DOI: 10.1101/gad.1770109. View

11.

Gopalsamy A, Bennett E, Shi M, Zhang W, Bard J, Yu K . Identification of pyrimidine derivatives as hSMG-1 inhibitors. Bioorg Med Chem Lett. 2012; 22(21):6636-41. DOI: 10.1016/j.bmcl.2012.08.107. View

12.

Weischenfeldt J, Waage J, Tian G, Zhao J, Damgaard I, Jakobsen J . Mammalian tissues defective in nonsense-mediated mRNA decay display highly aberrant splicing patterns. Genome Biol. 2012; 13(5):R35. PMC: 3446288. DOI: 10.1186/gb-2012-13-5-r35. View

13.

Huntzinger E, Kashima I, Fauser M, Sauliere J, Izaurralde E . SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan. RNA. 2008; 14(12):2609-17. PMC: 2590965. DOI: 10.1261/rna.1386208. View

14.

Smith J, Alvarez-Dominguez J, Kline N, Huynh N, Geisler S, Hu W . Translation of small open reading frames within unannotated RNA transcripts in Saccharomyces cerevisiae. Cell Rep. 2014; 7(6):1858-66. PMC: 4105149. DOI: 10.1016/j.celrep.2014.05.023. View

15.

Colombo M, Karousis E, Bourquin J, Bruggmann R, Muhlemann O . Transcriptome-wide identification of NMD-targeted human mRNAs reveals extensive redundancy between SMG6- and SMG7-mediated degradation pathways. RNA. 2016; 23(2):189-201. PMC: 5238794. DOI: 10.1261/rna.059055.116. View

16.

Goetz A, Wilkinson M . Stress and the nonsense-mediated RNA decay pathway. Cell Mol Life Sci. 2017; 74(19):3509-3531. PMC: 5683946. DOI: 10.1007/s00018-017-2537-6. View

17.

Azzalin C, Lingner J . The human RNA surveillance factor UPF1 is required for S phase progression and genome stability. Curr Biol. 2006; 16(4):433-9. DOI: 10.1016/j.cub.2006.01.018. View

18.

Gewandter J, Bambara R, OReilly M . The RNA surveillance protein SMG1 activates p53 in response to DNA double-strand breaks but not exogenously oxidized mRNA. Cell Cycle. 2011; 10(15):2561-7. PMC: 3180194. DOI: 10.4161/cc.10.15.16347. View

19.

Pastor F, Kolonias D, Giangrande P, Gilboa E . Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay. Nature. 2010; 465(7295):227-30. PMC: 3107067. DOI: 10.1038/nature08999. View

20.

Khajavi M, Inoue K, Lupski J . Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease. Eur J Hum Genet. 2006; 14(10):1074-81. DOI: 10.1038/sj.ejhg.5201649. View