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Table 1 Physiological functions of NMD and its regulation in response to developmental and stress signals

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

Cellular/molecular processes NMD function and regulation Target genes References
Suppression of aberrant transcripts and transcriptional “noise” Targets mis-spliced or aberrantly transcribed RNAs, and those derived from mutant genes, transposons and retroviral DNA, for degradation Many [10, 49, 176]
Lymphocyte development Suppresses expression of unproductive rearrangements of immunoglobulin and Tcell receptor genes Immunoglobulin, T-cell receptors [5, 96, 97]
Embryonic stem cell differentiation Promotes differentiation by regulating c-myc and the TGFβ/BMP pathways C-Myc, Smad7 [6, 99, 100]
Neurogenesis Facilitates expression of neuron-specific NMD targets in differentiating neuronal stem cells through miR-128-mediated downregulation of NMD Many (e.g. Enpp2, Apoe, Abca1, Atp1a2, Kcnj10, Kcnd2, Ttyh1, Ppp2rb2, Stat3, Smad5, Chrdl1, Myt1, Pla2g7, Cercam, Dmd, Slc6a13) [90]
Myogenesis Facilitates expression of the NMD target myogenin because increased SMD activity leads to reduced NMD function Myogenin [112]
Cellular viability Suppresses expression of GADD45α, leading to inhibition of apoptosis GADD45α [140]
lncRNA regulation May influence micropeptide expression from a subset of lncRNA transcripts ~17% of lncRNAs [129, 130]
Granulocyte differentiation Suppresses expression of genes that control granulocyte differentiation and morphology Dozens (e.g. Lmnb1) [98]
Axon guidance Guides axon migration by limiting the expression of Robo3.2 in commissural neurons Robo3.2 [109]
Synaptic regulation Impacts the expression of synaptic genes regulated by the RNA-binding protein NOVA, which is itself regulated by synaptic activity Many (e.g. Dlg3, Dzip1, Ahi1, Slc4a3, Slc4a10, Rasgrf1, Act16b, Scn9a, Stx2, Cdk5rap2, Stxbp2, Plekha5, Lrrcc1) [110]
Response to viral infection Targets viral RNAs to reduce viral load, but also downregulated by specific RNA elements or protein products (e.g. Tax and Rex) to protect viral RNAs Gag in RSV, HTLV-1 RNAs [114,115,116,117,118,119]
Stress response (e.g. amino acid deprivation, hypoxia, ER stress) Upregulates stress response genes as a consequence of downregulation of NMD activity by eIF2α phosphorylation Many (e.g. ATF4, ATF3, CHOP, IRE1α) [70, 73, 131,132,133,134,135,136]
Response to chemotherapeutics Upregulates pro-apoptotic NMD target genes, as a consequence of UPF1 cleavage by caspases during early stages of apoptosis that downregulates NMD GADD45α, GADD45β, BAK1, GAS5, DAP3, DUSP2 [138, 139]