Nonsense-mediated RNA decay (NMD) is a highly conserved RNA turnover pathway that selectively degrades RNAs harbouring truncating mutations that prematurely terminate translation, including nonsense, frameshift and some splice-site mutations. Recent studies show that NMD shapes the mutational landscape of tumours by selecting for mutations that tend to downregulate the expression of tumour suppressor genes but not oncogenes. This suggests that NMD can benefit tumours, a notion further supported by the finding that mRNAs encoding immunogenic neoantigen peptides are typically targeted for decay by NMD. Together, this raises the possibility that NMD-inhibitory therapy could be of therapeutic benefit against many tumour types, including those with a high load of neoantigen-generating mutations. Complicating this scenario is the evidence that NMD can also be detrimental for many tumour types, and consequently tumours often have perturbed NMD. NMD may suppress tumour generation and progression by degrading subsets of specific normal mRNAs, including those encoding stress-response proteins, signalling factors and other proteins beneficial for tumours, as well as pro-tumour non-coding RNAs. Together, these findings suggest that NMD-modulatory therapy has the potential to provide widespread therapeutic benefit against diverse tumour types. However, whether NMD should be stimulated or repressed requires careful analysis of the tumour to be treated.
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Galloway, A. & Cowling, V. H. mRNA cap regulation in mammalian cell function and fate. Biochim. Biophys. Acta Gene Regul. Mech. 1862, 270–279 (2019).
Pisera, A., Campo, A. & Campo, S. Structure and functions of the translation initiation factor eIF4E and its role in cancer development and treatment. J. Genet. Genomics 45, 13–24 (2018).
Stavraka, C. & Blagden, S. The La-related proteins, a family with connections to cancer. Biomolecules 5, 2701–2722 (2015).
Ghigna, C. et al. Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol. Cell 20, 881–890 (2005).
Karni, R. et al. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat. Struct. Mol. Biol. 14, 185–193 (2007).
Dvinge, H., Kim, E., Abdel-Wahab, O. & Bradley, R. K. RNA splicing factors as oncoproteins and tumour suppressors. Nat. Rev. Cancer 16, 413–430 (2016).
Kohler, A. & Hurt, E. Gene regulation by nucleoporins and links to cancer. Mol. Cell 38, 6–15 (2010).
Hautbergue, G. M. RNA nuclear export: from neurological disorders to cancer. Adv. Exp. Med. Biol. 1007, 89–109 (2017).
Cheadle, C. et al. Control of gene expression during T cell activation: alternate regulation of mRNA transcription and mRNA stability. BMC Genomics 6, 75 (2005).
Alonso, C. R. A complex ‘mRNA degradation code’ controls gene expression during animal development. Trends Genet. 28, 78–88 (2012).
Neff, A. T., Lee, J. Y., Wilusz, J., Tian, B. & Wilusz, C. J. Global analysis reveals multiple pathways for unique regulation of mRNA decay in induced pluripotent stem cells. Genome Res. 22, 1457–1467 (2012).
Munchel, S. E., Shultzaberger, R. K., Takizawa, N. & Weis, K. Dynamic profiling of mRNA turnover reveals gene-specific and system-wide regulation of mRNA decay. Mol. Biol. Cell 22, 2787–2795 (2011).
Hao, S. & Baltimore, D. The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules. Nat. Immunol. 10, 281–288 (2009).
Schoenberg, D. R. & Maquat, L. E. Regulation of cytoplasmic mRNA decay. Nat. Rev. Genet. 13, 246–259 (2012).
Jaffrey, S. R. & Wilkinson, M. F. Nonsense-mediated RNA decay in the brain: emerging modulator of neural development and disease. Nat. Rev. Neurosci. 19, 715–728 (2018).
Wolin, S. L. & Maquat, L. E. Cellular RNA surveillance in health and disease. Science 366, 822–827 (2019).
Nogueira, G., Fernandes, R., Garcia-Moreno, J. F. & Romao, L. Nonsense-mediated RNA decay and its bipolar function in cancer. Mol. Cancer 20, 72 (2021).
Kurosaki, T., Popp, M. W. & Maquat, L. E. Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nat. Rev. Mol. Cell Biol. 20, 406–420 (2019).
Hwang, J. & Maquat, L. E. Nonsense-mediated mRNA decay (NMD) in animal embryogenesis: to die or not to die, that is the question. Curr. Opin. Genet. Dev. 21, 422–430 (2011).
Goetz, A. E. & Wilkinson, M. Stress and the nonsense-mediated RNA decay pathway. Cell Mol. Life Sci. 74, 3509–3531 (2017).
Chang, J. C. & Kan, Y. W. beta 0 thalassemia, a nonsense mutation in man. Proc. Natl Acad. Sci. USA 76, 2886–2889 (1979).
Losson, R. & Lacroute, F. Interference of nonsense mutations with eukaryotic messenger RNA stability. Proc. Natl Acad. Sci. USA 76, 5134–5137 (1979).
Jung, H. et al. Intron retention is a widespread mechanism of tumor-suppressor inactivation. Nat. Genet. 47, 1242–1248 (2015).
Perrin-Vidoz, L., Sinilnikova, O. M., Stoppa-Lyonnet, D., Lenoir, G. M. & Mazoyer, S. The nonsense-mediated mRNA decay pathway triggers degradation of most BRCA1 mRNAs bearing premature termination codons. Hum. Mol. Genet. 11, 2805–2814 (2002).
Ware, M. D. et al. Does nonsense-mediated mRNA decay explain the ovarian cancer cluster region of the BRCA2 gene? Oncogene 25, 323–328 (2006).
Karam, R. et al. The NMD mRNA surveillance pathway downregulates aberrant E-cadherin transcripts in gastric cancer cells and in CDH1 mutation carriers. Oncogene 27, 4255–4260 (2008).
Anczukow, O. et al. Does the nonsense-mediated mRNA decay mechanism prevent the synthesis of truncated BRCA1, CHK2, and p53 proteins? Hum. Mutat. 29, 65–73 (2008). This study is the first to show different roles for PTCs in tumour suppressor genes. PTCs could elicit NMD or destabilize the final protein product, leading in either case to lower overall protein levels.
Zientek-Targosz, H. et al. Transformation of MCF-10A cells by random mutagenesis with frameshift mutagen ICR191: a model for identifying candidate breast-tumor suppressors. Mol. Cancer 7, 51 (2008).
Ionov, Y., Nowak, N., Perucho, M., Markowitz, S. & Cowell, J. K. Manipulation of nonsense mediated decay identifies gene mutations in colon cancer cells with microsatellite instability. Oncogene 23, 639–645 (2004).
Ivanov, I., Lo, K. C., Hawthorn, L., Cowell, J. K. & Ionov, Y. Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediated mRNA decay in colon cancer cells. Oncogene 26, 2873–2884 (2007). This study uses a novel screen — involving mutagenesis followed by NMD inhibition — to identify known and novel candidate tumour suppressor genes.
Rossi, M. R. et al. Identification of inactivating mutations in the JAK1, SYNJ2, and CLPTM1 genes in prostate cancer cells using inhibition of nonsense-mediated decay and microarray analysis. Cancer Genet. Cytogenet. 161, 97–103 (2005).
Lindeboom, R. G., Supek, F. & Lehner, B. The rules and impact of nonsense-mediated mRNA decay in human cancers. Nat. Genet. 48, 1112–1118 (2016). This study analyses the mutational landscape and gene expression patterns of ~10,000 human tumours, allowing ‘NMD rules’ to be defined that dictate whether a PTC mutation elicits NMD. The authors also use these datasets to identify classes of genes undergoing positive and negative selection for ‘NMD-elicit’ PTC mutations in tumours.
Lindeboom, R. G. H., Vermeulen, M., Lehner, B. & Supek, F. The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy. Nat. Genet. 51, 1645–1651 (2019). This study examines the impact of NMD on cancer and genetic diseases. It also generates NMDetective, a resource that predicts whether NMD is triggered by a given PTC-generating mutation.
Hu, Z., Yau, C. & Ahmed, A. A. A pan-cancer genome-wide analysis reveals tumour dependencies by induction of nonsense-mediated decay. Nat. Commun. 8, 15943 (2017). This genome-wide study classifies tumours with respect to classes of genes enriched in ‘NMD-elicit’ mutations. This revealed that tumour types differ with respect to the profile of tumour suppressor genes that tended to be downregulated by NMD.
Pastor, F., Kolonias, D., Giangrande, P. H. & Gilboa, E. Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay. Nature 465, 227–230 (2010). This study reports the discovery that inhibiting NMD suppresses tumour cell growth and increases T cell infiltration in various subcutaneous and metastatic mouse tumour models.
Nossal, G. J. Cellular mechanisms of immunologic tolerance. Annu. Rev. Immunol. 1, 33–62 (1983).
Litchfield, K. et al. Escape from nonsense-mediated decay associates with anti-tumor immunogenicity. Nat. Commun. 11, 3800 (2020). This study shows — at the genome-wide level — that frameshift mutated transcripts (encoding neoantigens) that are insensitive to NMD tend to elicit antitumour immune responses.
Wang, D. et al. Inhibition of nonsense-mediated RNA decay by the tumor microenvironment promotes tumorigenesis. Mol. Cell Biol. 31, 3670–3680 (2011). This study demonstrates that inhibited NMD promotes tumorigenesis. The authors also provide evidence that the tumour microenvironment inhibits NMD in vivo.
Li, L. et al. The human RNA surveillance factor UPF1 modulates gastric cancer progression by targeting long non-coding RNA MALAT1. Cell Physiol. Biochem. 42, 2194–2206 (2017).
Chang, L. et al. The human RNA surveillance factor UPF1 regulates tumorigenesis by targeting Smad7 in hepatocellular carcinoma. J. Exp. Clin. Canc. Res. https://doi.org/10.1186/s13046-016-0286-2 (2016).
Lu, J. et al. The nonsense-mediated RNA decay pathway is disrupted in inflammatory myofibroblastic tumors. J. Clin. Invest. 126, 3058–3062 (2016).
Cao, L. et al. Human nonsense-mediated RNA decay regulates EMT by targeting the TGF-ss signaling pathway in lung adenocarcinoma. Cancer Lett. 403, 246–259 (2017). This study reports evidence that NMD inhibits EMT through regulation of TGFβ signalling in lung adenocarcinomas, thereby providing a potential mechanism by which NMD suppresses malignancy.
Liu, C. et al. The UPF1 RNA surveillance gene is commonly mutated in pancreatic adenosquamous carcinoma. Nat. Med. 20, 596–598 (2014).
Zhou, Y. et al. UPF1 inhibits the hepatocellular carcinoma progression by targeting long non-coding RNA UCA1. Sci. Rep. 9, 6652 (2019).
Chang, Y. F., Imam, J. S. & Wilkinson, M. F. The nonsense-mediated decay RNA surveillance pathway. Annu. Rev. Biochem. 76, 51–74 (2007).
Supek, F., Lehner, B. & Lindeboom, R. G. H. To NMD or not to NMD: nonsense-mediated mRNA decay in cancer and other genetic diseases. Trends Genet. https://doi.org/10.1016/j.tig.2020.11.002 (2020).
Leeds, P., Peltz, S. W., Jacobson, A. & Culbertson, M. R. The product of the yeast UPF1 gene is required for rapid turnover of mRNAs containing a premature translational termination codon. Genes Dev. 5, 2303–2314 (1991).
Gonzalez, C. I., Bhattacharya, A., Wang, W. & Peltz, S. W. Nonsense-mediated mRNA decay in Saccharomyces cerevisiae. Gene 274, 15–25 (2001).
Pulak, R. & Anderson, P. mRNA surveillance by the Caenorhabditis elegans smg genes. Genes Dev. 7, 1885–1897 (1993).
Lloyd, J. P. B. The evolution and diversity of the nonsense-mediated mRNA decay pathway. F1000Res 7, 1299 (2018).
Holbrook, J. A., Neu-Yilik, G., Hentze, M. W. & Kulozik, A. E. Nonsense-mediated decay approaches the clinic. Nat. Genet. 36, 801–808 (2004).
Inoue, K. et al. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat. Genet. 36, 361–369 (2004).
Thein, S. L. et al. Molecular basis for dominantly inherited inclusion body beta-thalassemia. Proc. Natl Acad. Sci. USA 87, 3924–3928 (1990).
Lelivelt, M. J. & Culbertson, M. R. Yeast Upf proteins required for RNA surveillance affect global expression of the yeast transcriptome. Mol. Cell Biol. 19, 6710–6719 (1999).
Mendell, J. T., Sharifi, N. A., Meyers, J. L., Martinez-Murillo, F. & Dietz, H. C. Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nat. Genet. 36, 1073–1078 (2004).
He, F. et al. Genome-wide analysis of mRNAs regulated by the nonsense-mediated and 5’ to 3’ mRNA decay pathways in yeast. Mol. Cell 12, 1439–1452 (2003).
Karousis, E. D. & Muhlemann, O. Nonsense-mediated mRNA decay begins where translation ends. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a032862 (2019).
Nasif, S., Contu, L. & Muhlemann, O. Beyond quality control: the role of nonsense-mediated mRNA decay (NMD) in regulating gene expression. Semin. Cell Dev. Biol. 75, 78–87 (2018).
Vicente-Crespo, M. & Palacios, I. M. Nonsense-mediated mRNA decay and development: shoot the messenger to survive? Biochem. Soc. Trans. 38, 1500–1505 (2010).
Medghalchi, S. M. et al. Rent1, a trans-effector of nonsense-mediated mRNA decay, is essential for mammalian embryonic viability. Hum. Mol. Genet. 10, 99–105 (2001).
Li, T. et al. Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay. EMBO J. 34, 1630–1647 (2015).
McIlwain, D. R. et al. Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense-mediated mRNA decay. Proc. Natl Acad. Sci. USA 107, 12186–12191 (2010).
Longman, D., Plasterk, R. H., Johnstone, I. L. & Caceres, J. F. Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway. Genes Dev. 21, 1075–1085 (2007).
Alonso, C. R. & Akam, M. A Hox gene mutation that triggers nonsense-mediated RNA decay and affects alternative splicing during Drosophila development. Nucleic Acids Res. 31, 3873–3880 (2003).
Anastasaki, C., Longman, D., Capper, A., Patton, E. E. & Caceres, J. F. Dhx34 and Nbas function in the NMD pathway and are required for embryonic development in zebrafish. Nucleic Acids Res. 39, 3686–3694 (2011).
Metzstein, M. M. & Krasnow, M. A. Functions of the nonsense-mediated mRNA decay pathway in Drosophila development. PLoS Genet. 2, e180 (2006).
Colak, D., Ji, S. J., Porse, B. T. & Jaffrey, S. R. Regulation of axon guidance by compartmentalized nonsense-mediated mRNA decay. Cell 153, 1252–1265 (2013).
Huang, L. et al. A Upf3b-mutant mouse model with behavioral and neurogenesis defects. Mol. Psychiatry 23, 1773–1786 (2018).
Tan, K. et al. The role of the NMD factor UPF3B in olfactory sensory neurons. eLife https://doi.org/10.7554/eLife.57525 (2020).
Han, X. et al. Nonsense-mediated mRNA decay: a ‘nonsense’ pathway makes sense in stem cell biology. Nucleic Acids Res. 46, 1038–1051 (2018).
Lejeune, F. Nonsense-mediated mRNA decay at the crossroads of many cellular pathways. BMB Rep. 50, 175–185 (2017).
Nelson, J. O., Moore, K. A., Chapin, A., Hollien, J. & Metzstein, M. M. Degradation of Gadd45 mRNA by nonsense-mediated decay is essential for viability. eLife https://doi.org/10.7554/eLife.12876 (2016).
Lou, C. H. et al. Posttranscriptional control of the stem cell and neurogenic programs by the nonsense-mediated RNA decay pathway. Cell Rep. 6, 748–764 (2014).
Karam, R. et al. The unfolded protein response is shaped by the NMD pathway. EMBO Rep. 16, 599–609 (2015).
Chan, W. K. et al. An alternative branch of the nonsense-mediated decay pathway. EMBO J. 26, 1820–1830 (2007).
Gehring, N. H. et al. Exon-junction complex components specify distinct routes of nonsense-mediated mRNA decay with differential cofactor requirements. Mol. Cell 20, 65–75 (2005).
Mabin, J. W. et al. The exon junction complex undergoes a compositional switch that alters mRNP structure and nonsense-mediated mRNA decay activity. Cell Rep. 25, 2431–2446 e2437 (2018).
Yi, Z., Sanjeev, M. & Singh, G. The branched nature of the nonsense-mediated mRNA decay pathway. Trends Genet. 37, 143–159 (2021).
Tarpey, P. S. et al. Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat. Genet. 39, 1127–1133 (2007).
Nguyen, L. S., Wilkinson, M. F. & Gecz, J. Nonsense-mediated mRNA decay: inter-individual variability and human disease. Neurosci. Biobehav. Rev. 46, 175–186 (2014).
Nagy, E. & Maquat, L. E. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem. Sci. 23, 198–199 (1998).
Cirulli, E. T. et al. A whole-genome analysis of premature termination codons. Genomics 98, 337–342 (2011).
Montgomery, S. B., Lappalainen, T., Gutierrez-Arcelus, M. & Dermitzakis, E. T. Rare and common regulatory variation in population-scale sequenced human genomes. PLoS Genet. 7, e1002144 (2011).
MacArthur, D. G. et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335, 823–828 (2012).
Lappalainen, T. et al. Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501, 506–511 (2013).
Rivas, M. A. et al. Effect of predicted protein-truncating genetic variants on the human transcriptome. Science 348, 666–669 (2015).
Martincorena, I. et al. Universal patterns of selection in cancer and somatic tissues. Cell 173, 1823 (2018).
Pereira, F. J. et al. Resistance of mRNAs with AUG-proximal nonsense mutations to nonsense-mediated decay reflects variables of mRNA structure and translational activity. Nucleic Acids Res. 43, 6528–6544 (2015).
Kishor, A., Ge, Z. & Hogg, J. R. hnRNP L-dependent protection of normal mRNAs from NMD subverts quality control in B cell lymphoma. EMBO J. https://doi.org/10.15252/embj.201899128 (2019). This study identifies specific cis elements in RNAs that allow NMD escape. The authors show that this escape mechanism permits survival of B cell lymphomas through stabilization of the mRNA encoding the oncoprotein BCL-2.
Ge, Z., Quek, B. L., Beemon, K. L. & Hogg, J. R. Polypyrimidine tract binding protein 1 protects mRNAs from recognition by the nonsense-mediated mRNA decay pathway. eLife https://doi.org/10.7554/eLife.11155 (2016).
Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306–313 (2012).
Mort, M., Ivanov, D., Cooper, D. N. & Chuzhanova, N. A. A meta-analysis of nonsense mutations causing human genetic disease. Hum. Mutat. 29, 1037–1047 (2008).
Gardner, L. B. Nonsense-mediated RNA decay regulation by cellular stress: implications for tumorigenesis. Mol. Cancer Res. 8, 295–308 (2010).
Pestova, T. V. et al. The joining of ribosomal subunits in eukaryotes requires eIF5B. Nature 403, 332–335 (2000).
Schaffler, K. et al. A stimulatory role for the La-related protein 4B in translation. RNA 16, 1488–1499 (2010).
Yang, R. et al. La-related protein 4 binds poly(A), interacts with the poly(A)-binding protein MLLE domain via a variant PAM2w motif, and can promote mRNA stability. Mol. Cell Biol. 31, 542–556 (2011).
Leslie, N. R. & Downes, C. P. PTEN function: how normal cells control it and tumour cells lose it. Biochem. J. 382, 1–11 (2004).
Luna, S. et al. A global analysis of the reconstitution of PTEN function by translational readthrough of PTEN pathogenic premature termination codons. Hum. Mutat. https://doi.org/10.1002/humu.24186 (2021).
Knudson, A. G. Jr. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 68, 820–823 (1971).
Jain, P. K. Epigenetics: the role of methylation in the mechanism of action of tumor suppressor genes. Ann. N. Y. Acad. Sci. 983, 71–83 (2003).
Gudikote, J. P. & Wilkinson, M. F. T-cell receptor sequences that elicit strong down-regulation of premature termination codon-bearing transcripts. EMBO J. 21, 125–134 (2002).
Buhler, M., Paillusson, A. & Muhlemann, O. Efficient downregulation of immunoglobulin mu mRNA with premature translation-termination codons requires the 5’-half of the VDJ exon. Nucleic Acids Res. 32, 3304–3315 (2004).
Gudikote, J. P., Imam, J. S., Garcia, R. F. & Wilkinson, M. F. RNA splicing promotes translation and RNA surveillance. Nat. Struct. Mol. Biol. 12, 801–809 (2005).
Kurosaki, T. et al. A post-translational regulatory switch on UPF1 controls targeted mRNA degradation. Genes Dev. 28, 1900–1916 (2014).
Park, S., Supek, F. & Lehner, B. Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers. Nat. Commun. 12, 7051 (2021).
de Vries, A. et al. Targeted point mutations of p53 lead to dominant-negative inhibition of wild-type p53 function. Proc. Natl Acad. Sci. USA 99, 2948–2953 (2002).
Boettcher, S. et al. A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science 365, 599–604 (2019).
Sylvain, V., Lafarge, S. & Bignon, Y. J. Dominant-negative activity of a Brca1 truncation mutant: effects on proliferation, tumorigenicity in vivo, and chemosensitivity in a mouse ovarian cancer cell line. Int. J. Oncol. 20, 845–853 (2002).
Turajlic, S. et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 18, 1009–1021 (2017). Using a genome-wide screening approach, this study evaluates the relationship between neoantigens and immune responses in cancer. Among the findings is the observation that frameshift-inducing deletions generated more predicted neoantigens than non-synonymous SNVs.
Hacohen, N., Fritsch, E. F., Carter, T. A., Lander, E. S. & Wu, C. J. Getting personal with neoantigen-based therapeutic cancer vaccines. Cancer Immunol. Res. 1, 11–15 (2013).
Kloor, M. & von Knebel Doeberitz, M. The immune biology of microsatellite-unstable cancer. Trends Cancer 2, 121–133 (2016).
Marrack, P. & Kappler, J. The T cell receptor. Science 238, 1073–1079 (1987).
Ballhausen, A. et al. The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution. Nat. Commun. 11, 4740 (2020).
Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol. 20, 651–668 (2020).
Robbins, P. F. et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19, 747–752 (2013).
Bassani-Sternberg, M. et al. Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry. Nat. Commun. 7, 13404 (2016).
Roh, W. et al. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aah3560 (2017).
Cristescu, R. et al. Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors. J. Immunother. Cancer https://doi.org/10.1136/jitc-2021-003091 (2022).
Livingstone, A. M. & Fathman, C. G. The structure of T-cell epitopes. Annu. Rev. Immunol. 5, 477–501 (1987).
Zhao, B. & Pritchard, J. R. Evolution of the nonsense-mediated decay pathway is associated with decreased cytolytic immune infiltration. PLoS Comput. Biol. 15, e1007467 (2019).
Becker, J. P. et al. NMD inhibition by 5-azacytidine augments presentation of immunogenic frameshift-derived neoepitopes. iScience 24, 102389 (2021). This study shows that inhibiting NMD stabilizes frameshifted neoantigen-encoding mRNAs and increases the presentation of some of the encoded neoantigens by class I human leukocyte antigen (HLA) molecules. The authors show that one of the recurrent frameshift mutations in an MSI CRC tumour encodes a highly immunogenic neoantigen that elicits strong cytotoxic T cell responses.
Bhuvanagiri, M. et al. 5-azacytidine inhibits nonsense-mediated decay in a MYC-dependent fashion. EMBO Mol. Med. 6, 1593–1609 (2014).
Mizojiri, R. et al. Discovery of novel 5-(piperazine-1-carbonyl)pyridin-2(1H)-one derivatives as orally eIF4A3-selective inhibitors. ACS Med. Chem. Lett. 8, 1077–1082 (2017).
Gonzalez-Hilarion, S. et al. Rescue of nonsense mutations by amlexanox in human cells. Orphanet J. Rare Dis. 7, 58 (2012).
Bokhari, A. et al. Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability. Oncogenesis 7, 70 (2018).
El-Bchiri, J. et al. Nonsense-mediated mRNA decay impacts MSI-driven carcinogenesis and anti-tumor immunity in colorectal cancers. PLoS ONE 3, e2583 (2008).
Zhu, C. et al. UPF1 promotes chemoresistance to oxaliplatin through regulation of TOP2A activity and maintenance of stemness in colorectal cancer. Cell Death Dis. 12, 519 (2021).
Shum, E. Y. et al. The antagonistic gene paralogs Upf3a and Upf3b govern nonsense-mediated RNA decay. Cell 165, 382–395 (2016).
Gotoh, M. et al. Comprehensive exploration of novel chimeric transcripts in clear cell renal cell carcinomas using whole transcriptome analysis. Genes Chromosomes Cancer 53, 1018–1032 (2014).
Michalak, M. et al. (Phospho)proteomic profiling of microsatellite unstable CRC cells reveals alterations in nuclear signaling and cholesterol metabolism caused by frameshift mutation of NMD regulator UPF3A. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21155234 (2020).
Gardner, L. B. Hypoxic inhibition of nonsense-mediated RNA decay regulates gene expression and the integrated stress response. Mol. Cell Biol. 28, 3729–3741 (2008).
Pei, C. L., Fei, K. L., Yuan, X. Y. & Gong, X. J. LncRNA DANCR aggravates the progression of ovarian cancer by downregulating UPF1. Eur. Rev. Med. Pharmacol. Sci. 23, 10657–10663 (2019).
Lv, Z. H., Wang, Z. Y. & Li, Z. Y. LncRNA PVT1 aggravates the progression of glioma via downregulating UPF1. Eur. Rev. Med. Pharmacol. Sci. 23, 8956–8963 (2019).
Zhang, H., You, Y. & Zhu, Z. The human RNA surveillance factor Up-frameshift 1 inhibits hepatic cancer progression by targeting MRP2/ABCC2. Biomed. Pharmacother. 92, 365–372 (2017).
Polaski, J. T. et al. The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma. eLife 7554/eLife.62209 (2021).
Jo, Y. S., Song, S. Y., Kim, M. S., Yoo, N. J. & Lee, S. H. Frameshift mutations of SMG7 essential for nonsense-mediated mRNA decay in gastric and colorectal cancers. Pathol. Oncol. Res. 23, 221–222 (2017).
Bao, X., Huang, Y., Xu, W. & Xiong, G. Functions and clinical significance of UPF3a expression in human colorectal cancer. Cancer Manag. Res. 12, 4271–4281 (2020).
Sirkisoon, S. R. et al. Interaction between STAT3 and GLI1/tGLI1 oncogenic transcription factors promotes the aggressiveness of triple-negative breast cancers and HER2-enriched breast cancer. Oncogene 37, 2502–2514 (2018).
Tani, H. et al. Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability. RNA Biol. 9, 1370–1379 (2012).
Schmidt, S. A. et al. Identification of SMG6 cleavage sites and a preferred RNA cleavage motif by global analysis of endogenous NMD targets in human cells. Nucleic Acids Res. 43, 309–323 (2015).
Huang, L. et al. RNA homeostasis governed by cell type-specific and branched feedback loops acting on NMD. Mol. Cell 43, 950–961 (2011).
Yepiskoposyan, H., Aeschimann, F., Nilsson, D., Okoniewski, M. & Muhlemann, O. Autoregulation of the nonsense-mediated mRNA decay pathway in human cells. RNA 17, 2108–2118 (2011).
Cho, H. et al. SMG5-PNRC2 is functionally dominant compared with SMG5-SMG7 in mammalian nonsense-mediated mRNA decay. Nucleic Acids Res. 41, 1319–1328 (2013).
Karousis, E. D., Gypas, F., Zavolan, M. & Muhlemann, O. Nanopore sequencing reveals endogenous NMD-targeted isoforms in human cells. Genome Biol. 22, 223 (2021).
Lykke-Andersen, S. et al. Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes. Genes Dev. 28, 2498–2517 (2014).
Lou, C. H. et al. Nonsense-mediated RNA decay influences human embryonic stem cell fate. Stem Cell Rep. 6, 844–857 (2016).
You, B. et al. Androgen receptor promotes renal cell carcinoma (RCC) vasculogenic mimicry (VM) via altering TWIST1 nonsense-mediated decay through lncRNA-TANAR. Oncogene 40, 1674–1689 (2021).
Rasti, A. et al. Cytoplasmic expression of Twist1, an EMT-related transcription factor, is associated with higher grades renal cell carcinomas and worse progression-free survival in clear cell renal cell carcinoma. Clin. Exp. Med. 18, 177–190 (2018).
Rossello-Tortella, M. et al. Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer. Proc. Natl Acad. Sci. USA 117, 20785–20793 (2020).
Valacca, C. et al. Sam68 regulates EMT through alternative splicing-activated nonsense-mediated mRNA decay of the SF2/ASF proto-oncogene. J. Cell Biol. 191, 87–99 (2010).
He, J. & Ma, X. Interaction between lncRNA and UPF1 in tumors. Front. Genet. 12, 624905 (2021).
Chen, B. L., Wang, H. M., Lin, X. S. & Zeng, Y. M. UPF1: a potential biomarker in human cancers. Front. Biosci. 26, 76–84 (2021).
Andjus, S., Morillon, A. & Wery, M. From yeast to mammals, the nonsense-mediated mRNA decay as a master regulator of long non-coding RNAs functional trajectory. Noncoding RNA https://doi.org/10.3390/ncrna7030044 (2021).
Aspden, J. L. et al. Extensive translation of small open reading frames revealed by Poly-Ribo-Seq. eLife 3, e03528 (2014).
Ruiz-Orera, J., Messeguer, X., Subirana, J. A. & Alba, M. M. Long non-coding RNAs as a source of new peptides. eLife 3, e03523 (2014).
Anderson, D. M. et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell 160, 595–606 (2015).
Guerra-Almeida, D. & Nunes-da-Fonseca, R. Small open reading frames: how important are they for molecular evolution? Front. Genet. 11, 574737 (2020).
Gutschner, T. et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 73, 1180–1189 (2013).
Meseure, D. et al. Prognostic value of a newly identified MALAT1 alternatively spliced transcript in breast cancer. Br. J. Cancer 114, 1395–1404 (2016).
Malakar, P. et al. Long noncoding RNA MALAT1 promotes hepatocellular carcinoma development by SRSF1 upregulation and mTOR activation. Cancer Res. 77, 1155–1167 (2017).
Lee, N. K. et al. MALAT1 promoted invasiveness of gastric adenocarcinoma. BMC Cancer 17, 46 (2017).
Gong, C., Kim, Y. K., Woeller, C. F., Tang, Y. & Maquat, L. E. SMD and NMD are competitive pathways that contribute to myogenesis: effects on PAX3 and myogenin mRNAs. Genes Dev. 23, 54–66 (2009).
Park, E. & Maquat, L. E. Staufen-mediated mRNA decay. Wiley Interdiscip. Rev. RNA 4, 423–435 (2013).
Chang, L. et al. Upregulation of SNHG6 regulates ZEB1 expression by competitively binding miR-101-3p and interacting with UPF1 in hepatocellular carcinoma. Cancer Lett. 383, 183–194 (2016).
Karam, R., Wengrod, J., Gardner, L. B. & Wilkinson, M. F. Regulation of nonsense-mediated mRNA decay: implications for physiology and disease. Biochim. Biophys. Acta 1829, 624–633 (2013).
Huang, L. & Wilkinson, M. F. Regulation of nonsense-mediated mRNA decay. Wiley Interdiscip. Rev. RNA 3, 807–828 (2012).
Bruno, I. G. et al. Identification of a microRNA that activates gene expression by repressing nonsense-mediated RNA decay. Mol. Cell 42, 500–510 (2011).
Wang, D., Wengrod, J. & Gardner, L. B. Overexpression of the c-myc oncogene inhibits nonsense-mediated RNA decay in B lymphocytes. J. Biol. Chem. 286, 40038–40043 (2011).
Hetz, C. & Saxena, S. ER stress and the unfolded protein response in neurodegeneration. Nat. Rev. Neurol. 13, 477–491 (2017).
Zhao, L. & Ackerman, S. L. Endoplasmic reticulum stress in health and disease. Curr. Opin. Cell Biol. 18, 444–452 (2006).
Chawla, R. et al. Human UPF1 interacts with TPP1 and telomerase and sustains telomere leading-strand replication. EMBO J. 30, 4047–4058 (2011).
Ngo, G. H. P., Grimstead, J. W. & Baird, D. M. UPF1 promotes the formation of R loops to stimulate DNA double-strand break repair. Nat. Commun. 12, 3849 (2021).
Lavysh, D. & Neu-Yilik, G. UPF1-mediated RNA decay — Danse Macabre in a cloud. Biomolecules https://doi.org/10.3390/biom10070999 (2020).
Roberts, T. L. et al. Smg1 haploinsufficiency predisposes to tumor formation and inflammation. Proc. Natl Acad. Sci. USA 110, E285–E294 (2013).
Gupta, D. et al. Case series of outcomes in advanced cancer patients with single pathway alterations receiving N-of-one therapies. NPJ Precis. Oncol. 6, 18 (2022).
Alexandrov, A., Shu, M. D. & Steitz, J. A. Fluorescence amplification method for forward genetic discovery of factors in human mRNA degradation. Mol. Cell 65, 191–201 (2017).
Boelz, S., Neu-Yilik, G., Gehring, N. H., Hentze, M. W. & Kulozik, A. E. A chemiluminescence-based reporter system to monitor nonsense-mediated mRNA decay. Biochem. Biophys. Res. Commun. 349, 186–191 (2006).
Paillusson, A., Hirschi, N., Vallan, C., Azzalin, C. M. & Muhlemann, O. A GFP-based reporter system to monitor nonsense-mediated mRNA decay. Nucleic Acids Res. 33, e54 (2005).
Wang, M. et al. Assessing the activity of nonsense-mediated mRNA decay in lung cancer. BMC Med. Genomics 10, 55 (2017).
Dang, Y. et al. Inhibition of nonsense-mediated mRNA decay by the natural product pateamine A through eukaryotic initiation factor 4AIII. J. Biol. Chem. 284, 23613–23621 (2009).
Yamashita, A., Ohnishi, T., Kashima, I., Taya, Y. & Ohno, S. Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay. Genes Dev. 15, 2215–2228 (2001).
Martinez-Nunez, R. T. et al. Modulation of nonsense mediated decay by rapamycin. Nucleic Acids Res. 45, 3448–3459 (2017).
Bordonaro, M. & Lazarova, D. Amlexanox and UPF1 modulate Wnt signaling and apoptosis in HCT-116 colorectal cancer cells. J. Cancer 10, 287–292 (2019).
Durand, S. et al. Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies. J. Cell Biol. 178, 1145–1160 (2007).
Palma, M. et al. A role for AKT1 in nonsense-mediated mRNA decay. Nucleic Acids Res. 49, 11022–11037 (2021).
Zhao, J. et al. Molecular profiling of individual FDA-approved clinical drugs identifies modulators of nonsense-mediated mRNA decay. Mol. Ther. Nucleic Acids 27, 304–318 (2022).
Martin, L. et al. Identification and characterization of small molecules that inhibit nonsense-mediated RNA decay and suppress nonsense p53 mutations. Cancer Res. 74, 3104–3113 (2014).
Iwatani-Yoshihara, M. et al. Discovery and characterization of a eukaryotic initiation factor 4A-3-selective inhibitor that suppresses nonsense-mediated mRNA decay. ACS Chem. Biol. 12, 1760–1768 (2017).
Kungwankiattichai, S. et al. Maintenance with hypomethylating agents after allogeneic stem cell transplantation in acute myeloid leukemia and myelodysplastic syndrome: a systematic review and meta-analysis. Front. Med. 9, 801632 (2022).
Pal, M., Ishigaki, Y., Nagy, E. & Maquat, L. E. Evidence that phosphorylation of human Upfl protein varies with intracellular location and is mediated by a wortmannin-sensitive and rapamycin-sensitive PI 3-kinase-related kinase signaling pathway. RNA 7, 5–15 (2001).
Yakhni, M. et al. Homoharringtonine, an approved anti-leukemia drug, suppresses triple negative breast cancer growth through a rapid reduction of anti-apoptotic protein abundance. Am. J. Cancer Res. 9, 1043–1060 (2019).
Pedersen, S., Celis, J. E., Nielsen, J., Christiansen, J. & Nielsen, F. C. Distinct repression of translation by wortmannin and rapamycin. Eur. J. Biochem. 247, 449–456 (1997).
Usuki, F. et al. Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity. Proc. Natl Acad. Sci. USA 110, 15037–15042 (2013).
Xu, W. et al. Reactivation of nonsense-mediated mRNA decay protects against C9orf72 dipeptide-repeat neurotoxicity. Brain 142, 1349–1364 (2019).
CMP Health Care Media. Cancer Management: A Multi-disciplinary Approach, Medical, Surgical & Radiation Oncology. 13th edn (CMP Health Care Media, 2011).
Popp, M. W. & Maquat, L. E. Attenuation of nonsense-mediated mRNA decay facilitates the response to chemotherapeutics. Nat. Commun. 6, 6632 (2015). This study is among the first to provide proof of principle that NMD-modulatory therapy exhibits efficacy in promoting tumour cell death when used in combination with other chemotherapeutic agents.
Tani, H., Torimura, M. & Akimitsu, N. The RNA degradation pathway regulates the function of GAS5 a non-coding RNA in mammalian cells. PLoS ONE 8, e55684 (2013).
Cowen, L. E. & Tang, Y. Identification of nonsense-mediated mRNA decay pathway as a critical regulator of p53 isoform beta. Sci. Rep. 7, 17535 (2017).
Reddy, J. C. et al. WT1-mediated transcriptional activation is inhibited by dominant negative mutant proteins. J. Biol. Chem. 270, 10878–10884 (1995).
McMahon, S. B. MYC and the control of apoptosis. Cold Spring Harb. Perspect. Med. 4, a014407 (2014).
Jinesh, G. G., Sambandam, V., Vijayaraghavan, S., Balaji, K. & Mukherjee, S. Molecular genetics and cellular events of K-Ras-driven tumorigenesis. Oncogene 37, 839–846 (2018).
Kim, E. et al. SRSF2 mutations contribute to myelodysplasia by mutant-specific effects on exon recognition. Cancer Cell 27, 617–630 (2015).
Rahman, M. A., Lin, K. T., Bradley, R. K., Abdel-Wahab, O. & Krainer, A. R. Recurrent SRSF2 mutations in MDS affect both splicing and NMD. Genes Dev. 34, 413–427 (2020).
Gudikote, J. P. et al. Inhibition of nonsense-mediated decay rescues p53beta/gamma isoform expression and activates the p53 pathway in MDM2-overexpressing and select p53-mutant cancers. J. Biol. Chem. https://doi.org/10.1016/j.jbc.2021.101163 (2021). This study provides evidence that inhibiting NMD triggers tumour cell apoptosis and enhanced tumour radiosensitivity by stabilizing two alternatively spliced forms of p53 that are largely insensitive to repression by the p53 negative regulator MDM2.
Lee, S. R., Pratt, G. A., Martinez, F. J., Yeo, G. W. & Lykke-Andersen, J. Target discrimination in nonsense-mediated mRNA decay requires Upf1 ATPase activity. Mol. Cell 59, 413–425 (2015).
Kurosaki, T. & Maquat, L. E. Nonsense-mediated mRNA decay in humans at a glance. J. Cell Sci. 129, 461–467 (2016).
Buchwald, G. et al. Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC-UPF3b complex. Proc. Natl Acad. Sci. USA 107, 10050–10055 (2010).
Bono, F., Ebert, J., Lorentzen, E. & Conti, E. The crystal structure of the exon junction complex reveals how it maintains a stable grip on mRNA. Cell 126, 713–725 (2006).
Ni, Y. et al. The role of tumor-stroma interactions in drug resistance within tumor microenvironment. Front. Cell Dev. Biol. 9, 637675 (2021).
Al Tameemi, W., Dale, T. P., Al-Jumaily, R. M. K. & Forsyth, N. R. Hypoxia-modified cancer cell metabolism. Front. Cell Dev. Biol. 7, 4 (2019).
Daskalaki, I., Gkikas, I. & Tavernarakis, N. Hypoxia and selective autophagy in cancer development and therapy. Front. Cell Dev. Biol. 6, 104 (2018).
Senft, D. & Ronai, Z. A. Adaptive stress responses during tumor metastasis and dormancy. Trends Cancer 2, 429–442 (2016).
Saavedra-Garcia, P. et al. Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2018229118 (2021).
Popp, M. W. & Maquat, L. E. Nonsense-mediated mRNA decay and cancer. Curr. Opin. Genet Dev. 48, 44–50 (2018).
Ruhle, A. et al. Hypoxia dynamics on FMISO-PET in combination with PD-1/PD-L1 expression has an impact on the clinical outcome of patients with head-and-neck squamous cell carcinoma undergoing chemoradiation. Theranostics 10, 9395–9406 (2020).
Saxena, K. & Jolly, M. K. Acute vs. chronic vs. cyclic hypoxia: their differential dynamics, molecular mechanisms, and effects on tumor progression. Biomolecules https://doi.org/10.3390/biom9080339 (2019).
Oakes, S. A. Endoplasmic reticulum stress signaling in cancer cells. Am. J. Pathol. 190, 934–946 (2020).
Friedl, P. & Alexander, S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147, 992–1009 (2011).
Fendt, S. M., Frezza, C. & Erez, A. Targeting metabolic plasticity and flexibility dynamics for cancer therapy. Cancer Discov. 10, 1797–1807 (2020).
This study was funded by NIH R01 HD093846 (M.F.W.), as well as NIH R01 CA247562 and NIH R01 CA244182 (D.G.S.).
The authors declare no competing interests.
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- RNA turnover
Degradation of RNAs; typically achieved through the action of specific nucleases.
- Premature termination codons
(PTCs). Stop codons created by a mutation that prematurely terminates translation. PTC-bearing genes encode truncated proteins.
- Nonsense mutations
Substitutions of a single base pair that leads to the appearance of a stop codon where previously there was a codon specifying an amino acid.
- Frameshift mutations
Insertions and deletions downstream of the initiator codon that are not a multiple of 3, thereby shifting the reading frame. This results in a sequence of amino acids different from that in the original protein. Typically, a premature termination codon is also generated, which results in decay of the mRNA by nonsense-mediated RNA decay.
Non-self amino acid residue generated as a result of somatic mutations, including frameshift mutations. Such sequences are recognized as foreign when they are generated after the immune tolerance phase of fetal development.
- Untranslated region
(UTR). The region of an mRNA upstream and downstream of the coding region. The 5′ UTR is upstream of the initiator codon and the 3′ UTR is downstream of the stop codon.
- Passenger mutations
Mutations that have no discernible effect on cell fitness but are associated with clonal expansion simply because they occur in the same genome that harbours driver mutations.
- Missense mutations
Genetic alterations in which a single base pair substitution alters the genetic code in a way that produces an amino acid that is different from the usual amino acid at that position.
- Synonymous mutations
Changes in the DNA sequence that alter the codon but do not change the encoded amino acid (due to redundancy of the genetic code).
- PTC readthrough-inducing compounds
Small molecules that enable the ribosomal machinery to read a stop codon as a codon encoding an amino acid, often resulting in the expression of a full-length functional protein.
- Exon-junction complex
A protein complex deposited near most exon–exon junctions following RNA splicing. It stimulates nonsense-mediated RNA decay and also regulates several other post-transcriptional events.
- Dominant-negative proteins
Mutant proteins that antagonize the function of the wild type protein.
- Microsatellite instability
(MSI). Deficient DNA mismatch repair in tumours, which as a consequence makes them prone to hypermutation.
- Immune checkpoint inhibitors
(ICIs). Drugs that block checkpoint proteins (negative regulatory proteins) in immune cells. ICI therapy derepresses immune function and thereby enhances adaptive immune responses (that is, T cell and B cell responses).
- Epithelial-to-mesenchymal transition
(EMT). A critical developmental process co-opted by tumours in which epithelial cells acquire mesenchymal traits, including their migratory and invasive properties.
- Staufen-mediated mRNA decay
An mRNA decay pathway in competition with nonsense-mediated RNA decay that depends on the RNA-binding protein Staufen 1 or Staufen 2 and the RNA helicase up-frameshift 1 (UPF1).
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Tan, K., Stupack, D.G. & Wilkinson, M.F. Nonsense-mediated RNA decay: an emerging modulator of malignancy. Nat Rev Cancer 22, 437–451 (2022). https://doi.org/10.1038/s41568-022-00481-2