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Review
. 2020 Mar 24;12(3):765.
doi: 10.3390/cancers12030765.

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

Kamila Pawlicka  1 , Umesh Kalathiya  2 , Javier Alfaro  1   2
Affiliations
Review

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

Kamila Pawlicka et al. Cancers (Basel). .

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.

Keywords: Cancer; NMD inhibition; Neoantigens; Nonsense-mediated mRNA decay; Premature termination codon.

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Conflict of interest statement

The authors declare no conflict of interest to disclose.

Figures

Figure 1
Figure 1
Schematic representation of domains and motifs of the nonsense-mediated mRNA decay (NMD) factors. (a) The NMD complex UPF: up-frameshift; SMG: suppressor of morphogenetic effect on genitalia; DHX34: DEAH box polypeptide 34; DCPC: the decapping complex; EJC: exon junction complex; CCR4-NOT: carbon catabolite repressor protein 4 (CCR4)–NOT deadenylase complex [31]. (b) For the UPF and SMG proteins: CH: cysteine-histidine rich domain; Stalk: RecA1 domain by two long ‘stalk’ helices; RecA1 and RecA2: RecA-like domains; 1B and 1C: subdomains within the helicase core; SQ: serine-glutamine rich domain; RRM: RNA recognition motif; EBM: exon junction binding motif; MIF4G: middle of 4G-like domains; UBD: UPF1-binding domain; PIN: PilT N-terminus domain; PC: C-terminal proline-rich region; HEAT: Huntingtin, elongation factor 3 (EF3), protein phosphatase 2A (PP2A), yeast kinase TOR1 domain; FAT: focal adhesion kinase domain; FRB: FKBP12-rapamycin-binding; PIKK: phosphatidylinositol 3-kinase-related protein kinase domain; FATC: C-terminal FAT domain; G-fold-like: domains involved in dimerization between SMG8-SMG9 [31,32,33].
Figure 2
Figure 2
The protein-protein and protein-RNA binding interface for the NMD components, from the Protein Data Bank database (http://www.rcsb.org/pdb) [31,32,33,34,36,103,104,105,106,107,108,109,110,111,112]. (a) NMD pathway schematic representations, and protein-protein interactions form the complex: UPF1-UPF2 (PDB: 2wjv) [34], UPF2-UPF3b (PDB: 1uw4) [36], SMG5-SMG7 (PDB: 3zhe) [105,112], SMG8-SMG9 (PDB: 5nkk) [106], SMG1–SMG8–SMG9 (PDB: 6syt) [107]. (b) The exon junction complex; Mago-Y14-eIF4AIII-Barentsz-UPF3b (PDB: 2xb2) [108] (Table 1). The H-bond analysis was performed using BIOVIA Discovery Studio Visualizer program [Dassault Systemes, BIOVIA Corp., San Diego, CA, USA].
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