SMG1 is a serine/threonine protein kinase that functions as a central coordinator of mRNA surveillance and genotoxic stress response. Its primary role involves phosphorylating UPF1 to initiate nonsense-mediated decay (NMD), which selectively eliminates mRNAs containing premature stop codons 1. SMG1 operates within the SURF complex (SMG1-UPF1-eRF1-eRF3) and associates with the exon junction complex through UPF2 to activate NMD 2. Mechanistically, SMG8 and SMG9 inhibit SMG1 kinase activity through a kinase inhibitory domain; GTP hydrolysis of SMG9 restores SMG1 activity 1. Beyond NMD, SMG1 exhibits DNA damage response functions overlapping with ATM, phosphorylating p53 for optimal activation following genotoxic stress 3. SMG1 also regulates alternative splicing of TP53 pre-mRNA in DNA damage pathways, promoting cellular senescence independently of its NMD role 3. Clinical significance is substantial. Heterozygous SMG1 mutations causing reduced gene dosage impair NMD activity and affect nervous system development, associated with developmental delay and oculomotor apraxia 4. In cancer, IL-6/STAT3 signaling induces SMG1 expression, silencing frameshift-derived neoantigens through enhanced NMD, representing a novel immunoediting mechanism 5. Conversely, SMG1 inhibition increases neoantigen presentation on HLA class I molecules, enhancing immunotherapy responsiveness 6. KMT2D upregulates SMG1 to antagonize mTOR and induce ferroptosis in lymphomas 7.