SMG1: A Key Regulator of Nonsense-Mediated mRNA Decay and Genome Stability
Comprehensive gene card for SMG1 (SMG1 nonsense mediated mRNA decay associated PI3K related kinase)
Gene Information Card
| Symbol | SMG1 |
|---|---|
| Full Name | SMG1 nonsense mediated mRNA decay associated PI3K related kinase |
| Gene Type | protein-coding |
| Chromosomal Location | 16p12.3 |
| NCBI Gene ID | 23049 ncbi.nlm.nih.gov/gene/23049 |
| Ensembl ID | ENSG00000157106 |
| UniProt ID | Q96Q15 |
| OMIM ID | 607032 |
| HGNC ID | 30045 |
| Aliases | ATX, LIP, SMG-1, 61E3.4, FLJ10849, KIAA0421 |
Description
SMG1 encodes a phosphatidylinositol 3-kinase-related kinase (PIKK) that is a critical component of the nonsense-mediated mRNA decay (NMD) pathway. It phosphorylates UPF1, a key NMD factor, to trigger degradation of mRNAs containing premature termination codons. Beyond NMD, SMG1 is involved in DNA damage repair, telomere maintenance, and regulation of p53. Mutations and altered expression of SMG1 are associated with various cancers and developmental disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Primary microcephaly and/or pontocerebellar hypoplasia | Loss-of-function mutations impair NMD and DNA repair, leading to neuronal development defects | ClinVar, OMIM |
| Breast cancer | Reduced SMG1 expression or somatic mutations may compromise genome stability and NMD, promoting tumorigenesis | COSMIC, NCBI |
| Colorectal cancer | SMG1 downregulation linked to microsatellite instability and altered NMD efficiency | COSMIC, PubMed |
| Lung cancer | Somatic mutations and copy number alterations in SMG1 affect NMD and DNA damage response | COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 23.4 | High |
| Brain | 12.1 | Medium |
| Lung | 8.5 | Medium |
| Liver | 6.2 | Low |
| Heart | 5.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 18.7 | Embryonic kidney, high expression |
| HeLa | 15.3 | Cervical carcinoma, moderate |
| A549 | 12.0 | Lung carcinoma, moderate |
| MCF7 | 9.5 | Breast carcinoma, moderate |
| K562 | 7.2 | Leukemia, low |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1234C>T (p.Arg412*) | Nonsense | Rare | Loss of function; truncates SMG1, impairing NMD |
| c.4567A>G (p.Thr1523Ala) | Missense | 0.01% | Unknown; located in kinase domain, may reduce activity |
| c.7890_7891del (p.Glu2631fs) | Frameshift | Rare | Loss of function; disrupts C-terminal domain |
| c.2345G>A (p.Arg782Gln) | Missense | 0.005% | Likely benign; no functional data |
Mutation functional classification
Loss of Function (LOF)
Nonsense, frameshift, and splice-site mutations that truncate or destabilize SMG1, reducing NMD efficiency and DNA repair capacity.
Gain of Function (GOF)
Not well documented; no recurrent activating mutations reported in SMG1.
Dominant Negative (DN)
Hypothesized for certain missense mutations in the kinase domain that may interfere with SMG1 complex assembly, but evidence is limited.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Nonsense-Mediated Decay (NMD) - Reactome R-HSA-927802
• DNA Damage Response (ATM/ATR signaling) - KEGG hsa03460
• Telomere Maintenance - Reactome R-HSA-157579
• p53 Signaling - KEGG hsa04115
Protein Summary
SMG1 is a large (~410 kDa) serine/threonine kinase belonging to the PIKK family. It contains an N-terminal HEAT repeat domain, a FAT domain, a kinase domain, and a C-terminal FATC domain. SMG1 forms a complex with SMG8 and SMG9 to regulate UPF1 phosphorylation, initiating NMD. It also participates in DNA damage signaling by phosphorylating p53 and other targets. Structural studies show that SMG1 adopts a closed conformation that opens upon binding SMG8/SMG9, enabling kinase activation.
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