SMG1, a member of the PIKK (phosphoinositide 3-kinase related kinases) family, plays a critical role in the mRNA quality control system known as nonsense-mediated mRNA decay (NMD). NMD protects the cells from the accumulation of aberrant mRNAs with premature termination codons (PTCs) that encode nonfunctional or potentially harmful truncated proteins. SMG1 directly phosphorylates Upf1 helicase, another key component of NMD, and this phosphorylation occurs upon recognition of PTC on post-spliced mRNA during the initial round of translation. Phosphorylated-Upf1 recruits the SMG5:SMG7 complex to phospho-S1096 to induce ribosome dissociation and induce decapping mediated PTC-mRNA decay. Phospho-Upf1 also recruits SMG6 endonuclease to phospho-T28 which might be involved in PTC-mRNA end-cleavage. Upf1 ATPase/helicase activity are likely required for the activation of mRNA decay enzymes and mRNP dissociation to complete NMD. We will reveal the physiological significance of NMD, and the application of NMD mechanisms will open the new strategy for treatment of genetic diseases and cancer.