Dataset Information

Polymorphism (rs16917496) at the miR-502 Binding Site of the Lysine Methyltransferase 5A (SET8) and Its Correlation with Colorectal Cancer in Iranians.

ABSTRACT: BACKGROUND:One of the gene expression regulatory mechanisms is mediated by small noncoding RNAs called microRNA (miRNA). They interact with a recognition sequence located mostly in 3'-untranslated regions (3'-UTRs) of mRNAs. Polymorphisms in miRNAs recognition sequences could affect gene expression which in turn may alter disease susceptibility. SET8, a member of the SET domain-containing methyltransferase, acts in a variety of biological processes such as genomic stability. Here, we report correlation of rs16917496 polymorphism, located in the recognition sequence of miR-502 within 3'-UTR of SET8, with colorectal cancer (CRC) in Iranians. MATERIALS AND METHODS:One hundred and seventy CRC patients and 170 noncancer counterparts were recruited in this case-control study. Genotyping of rs16917496 was performed using polymerase chain reaction-restriction fragment length polymorphism method. RESULTS:There was no significant association of rs16917496 with CRC in population under study (P value for genotype and allele distribution were >0.05). However, stratification analysis based on smoking status revealed that TT+TC genotypes of SET8 rs16917496 are strongly associated with increased risk of CRC (odds ratio: 5.8, 95% confidence interval: 1.37-24.34, P - 0.005) in smoker subgroup. CONCLUSION:Correlation of rs16917496 T allele with CRC in smokers is emphasizing the importance of individuals' genotype in the recruitment of adverse health hazards of smoking more profoundly for certain people compared to others.

SUBMITTER: Mosallayi M

PROVIDER: S-EPMC5539672 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Polymorphism (rs16917496) at the miR-502 Binding Site of the Lysine Methyltransferase 5A (<i>SET8</i>) and Its Correlation with Colorectal Cancer in Iranians.

Mosallayi Meysam M Simonian Miganoosh M Khosravi Sharifeh S Salehi Ahmad Reza AR Khodadoostan Mahsa M Sebghatollahi Vahid V Baradaran Azar A Salehi Rasoul R

Advanced biomedical research 20170714

<h4>Background</h4>One of the gene expression regulatory mechanisms is mediated by small noncoding RNAs called microRNA (miRNA). They interact with a recognition sequence located mostly in 3'-untranslated regions (3'-UTRs) of mRNAs. Polymorphisms in miRNAs recognition sequences could affect gene expression which in turn may alter disease susceptibility. <i>SET8</i>, a member of the <i>SET</i> domain-containing methyltransferase, acts in a variety of biological processes such as genomic stability ...[more]

PMID: 28808643

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Project description:Protein lysine methyltransferases (PKMTs) catalyze the methylation of protein substrates, and their dysregulation has been linked to many diseases, including cancer. Accumulated evidence suggests that the reaction path of PKMT-catalyzed methylation consists of the formation of a cofactor(cosubstrate)-PKMT-substrate complex, lysine deprotonation through dynamic water channels, and a nucleophilic substitution (SN2) transition state for transmethylation. However, the molecular characters of the proposed process remain to be elucidated experimentally. Here we developed a matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) method and corresponding mathematic matrix to determine precisely the ratios of isotopically methylated peptides. This approach may be generally applicable for examining the kinetic isotope effects (KIEs) of posttranslational modifying enzymes. Protein lysine methyltransferase SET8 is the sole PKMT to monomethylate histone 4 lysine 20 (H4K20) and its function has been implicated in normal cell cycle progression and cancer metastasis. We therefore implemented the MS-based method to measure KIEs and binding isotope effects (BIEs) of the cofactor S-adenosyl-l-methionine (SAM) for SET8-catalyzed H4K20 monomethylation. A primary intrinsic 13C KIE of 1.04, an inverse intrinsic ?-secondary CD3 KIE of 0.90, and a small but statistically significant inverse CD3 BIE of 0.96, in combination with computational modeling, revealed that SET8-catalyzed methylation proceeds through an early, asymmetrical SN2 transition state with the C-N and C-S distances of 2.35-2.40 Å and 2.00-2.05 Å, respectively. This transition state is further supported by the KIEs, BIEs, and steady-state kinetics with the SAM analog Se-adenosyl-l-selenomethionine (SeAM) as a cofactor surrogate. The distinct transition states between protein methyltransferases present the opportunity to design selective transition-state analog inhibitors.

Dataset Information

Polymorphism (rs16917496) at the miR-502 Binding Site of the Lysine Methyltransferase 5A (SET8) and Its Correlation with Colorectal Cancer in Iranians.

Publications

Polymorphism (rs16917496) at the miR-502 Binding Site of the Lysine Methyltransferase 5A (<i>SET8</i>) and Its Correlation with Colorectal Cancer in Iranians.

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