SMG-1 (suppressor with morphogenetic effect on genitalia-1, SMG-1) is a newly discovered member of the phosphoinositide 3-kinase-related kinase (PIKKs) family. The sense-mediated mRNA degradation (nonsense-mediated mRNAdecay, NMD) pathway maintains genomic stability in genotoxic stress responses and participates in multiple biological processes such as cell growth, proliferation, and apoptosis. Therefore, it has been applied to tumor diseases. Significant results have been achieved in pathogenesis and treatment. This article will describe the research progress of SMG-1 in tumor diseases.

Figure 1. Protein structure of phosphoinositide 3-kinase-related kinase (PIKKs) family.

Introductions

In mammalian cells, the PIKK family includes 6 members, namely mammalian rapamycin target protein (mTOR), ataxia telangiectasia mutation gene (ATM), and ataxia telangiectasia Rad3-related proteins. (ATR), DNA-dependent protein kinase catalytic factor (DNA-PKcs), genital formation inhibitory gene (SMG-1), and transformation / transcription domain-related protein (TRRAP). Among them, SMG-1 is a newly discovered member, named after homology to the CeSMG-1 protein of C. elegans. cDNA library sequencing revealed that the SMG-1 gene encodes a protein containing 3031 amino acids, which contains a conserved kinase domain, a unique C-terminal domain of PIK-related kinases, and a binding site for the FKBP12-rapamycin complex Point domains (similar to those found in mTOR). People's understanding of SMG-1 begins with their participation in the non-sense-mediated mRNA degradation (non-sense mRNA decay (NMD) pathway), which can quickly identify and degrade premature termination caused by nonsense mutations or frameshift mutations. The codons (premature termination codons (PTC)) of mRNA avoid the production of potentially toxic truncated proteins. With the deepening of research, it has been found that SMG-1, like PIKK protein kinases such as ATM and ATR, also plays a role in maintaining genome stability in DNA damage repair. But the difference is that it also mediates a wider range of stress responses, including RNA damage. In order to further explore its value, some studies have confirmed that after the SMG-1 gene is knocked out or mutated, the sensitivity of tumor cells to chemoradiation and TNF-α-induced apoptosis is significantly improved, suggesting that the gene is anti-cancer drugs or radiation-induced tumors Damage is protective and may be one of the potential factors for tumor resistance and radiation resistance. Recent research shows that SMG-1 is also involved in regulating cell growth, proliferation, and even inhibiting tumor progression.

NND pathway

SMG-1 mediated NMD pathway: The NMD pathway is a highly conserved RNA surveillance mechanism widely found in eukaryotes in recent years, and it is also one of the more thoroughly researched SMG-1 mediated functions. The NMD pathway prevents the expression and accumulation of potentially toxic truncated proteins by rapidly recognizing and degrading non-sense mutation-containing transcription products containing premature termination codons, and this pathway can also regulate a small portion of normal transcription.

The role and value of SMG1 in stress response

With the increase of research investment, people have a more comprehensive understanding of SMG1. Researchers at home and abroad have found that SMG1 not only plays a key role in the NMD pathway, but also participates in DNA damage stress response and oxidative stress response. Hypoxia, and apoptosis. PIKK plays an important role in maintaining genome stability in coordinating multiple genotoxic stress responses, including nucleotide damage. Among them, ATM and DNA-PKcs mainly play a role in the response to DNA double-strand damage, while ATR is mainly involved in the stress response of single-stranded DNA damage and replication fork arrest, but there is no strict delimitation between them. Subsequent research confirmed that SMG-1 can also sense DNA damage, transduce DNA damage signals to downstream target proteins, activate the stress system through cascade amplification reactions, and induce phosphorylation of serine 15 site of p53 gene.

SMG -1 regulates growth and its relationship with tumors

SMG -1 regulates growth and its relationship with tumors. The SMG -1 gene is considered to be a neglected new tumor suppressor gene. The COSMIC database shows that mutations in the SMG -1 gene are present in breast, kidney and gastric cancers. Tumor cell lines have low expression levels of mRNA. Human protein mapping analysis report showed no SMG-1 expression in malignant lymphoma. Therefore, SMG-1 has the effect of inhibiting tumor formation, but if it is absent, it will greatly increase the probability of tumor development.

Reference

1. Yamashita A; et al. Human SMG -1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay. Genes Dev, 2001, 15 (17): 2215-2228.