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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]