Dataset Information

Polymorphisms in human telomerase reverse transcriptase (hTERT) gene, gene- gene and gene-smoking interaction with susceptibility to gastric cancer in Chinese Han population.

ABSTRACT: To investigate the association of telomerase reverse transcriptase (TERT) gene polymorphisms and additional gene-gene and gene- environment interaction with gastric cancer (GC) risk.GC risk was significantly higher in carriers of G allele of rs2736100 than those with TT genotype (TG+ GG versus TT), adjusted OR (95%CI) =1.68 (1.26-2.17), and higher in carriers of G allele of rs2853669 than those with AA genotype (AG+ GG versus AA), adjusted OR (95%CI) = 1.72 (1.19-2.33). We also found that interaction between rs2736100 and smoking was associated with higher GC risk. Smokers with TG or GG of rs2736100 genotype have elevated GC risk, compared to never- smokers with TT of rs2736100 genotype, OR (95%CI) = 3.12 (1.82 -4.61). Pairwise linkage equilibrium (LD) analysis between SNPs was measured and the D' value between rs2736100 and rs2736109 was more than 0.8. A haplotype containing the rs2736100- G and rs2736109- A alleles was associated with a statistically increased GC risk (OR= 2.66, 95%CI= 1.28 - 4.12, p<0.0001).A total of 1088 participants (686 males, 402 females) were selected, including 360 GC patients and 728 normal participants. Logistic regression was performed to investigate association between single nucleotide polymorphisms (SNPs) within TERT gene and GC susceptibility. Generalized multifactor dimensionality reduction (GMDR) model was used to screen gene- gene and gene- environment interaction combinations.We found that G allele of rs2736100 and G allele of rs2853669 in TERT gene, interaction between rs2736100 and smoking, and haplotype containing the rs2736100- G and rs2736109- A alleles were all associated with increased GC risk.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5386758 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Polymorphisms in human telomerase reverse transcriptase (hTERT) gene, gene- gene and gene-smoking interaction with susceptibility to gastric cancer in Chinese Han population.

Zhang Jian J Ju Hui H Gao Jun-Ru JR Jiao Xue-Long XL Lu Yun Y

Oncotarget 20170301 12

<h4>Aims</h4>To investigate the association of telomerase reverse transcriptase (TERT) gene polymorphisms and additional gene-gene and gene- environment interaction with gastric cancer (GC) risk.<h4>Results</h4>GC risk was significantly higher in carriers of G allele of rs2736100 than those with TT genotype (TG+ GG versus TT), adjusted OR (95%CI) =1.68 (1.26-2.17), and higher in carriers of G allele of rs2853669 than those with AA genotype (AG+ GG versus AA), adjusted OR (95%CI) = 1.72 (1.19-2.3 ...[more]

PMID: 28423629

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Project description:BackgroundTelomerase is a reverse transcriptase that maintains the telomeres of linear chromosomes and preserves genomic integrity. The core components are a catalytic protein subunit, the telomerase reverse transcriptase (TERT), and an RNA subunit, the telomerase RNA (TR). Telomerase is unique in its ability to catalyze processive DNA synthesis, which is facilitated by telomere-specific DNA-binding domains in TERT called anchor sites. A conserved glutamine residue in the TERT N-terminus is important for anchor site interactions in lower eukaryotes. The significance of this residue in higher eukaryotes, however, has not been investigated.Methodology/principal findingsTo understand the significance of this residue in higher eukaryotes, we performed site-directed mutagenesis on human TERT (hTERT) Q169 to create neutral (Q169A), conservative (Q169N), and non-conservative (Q169D) mutant proteins. We show that these mutations severely compromise telomerase activity in vitro and in vivo. The functional defects are not due to abrogated interactions with hTR or telomeric ssDNA. However, substitution of hTERT Q169 dramatically impaired the ability of telomerase to incorporate nucleotides at the second position of the template. Furthermore, Q169 mutagenesis altered the relative strength of hTERT-telomeric ssDNA interactions, which identifies Q169 as a novel residue in hTERT required for optimal primer binding. Proteolysis experiments indicate that Q169 substitution alters the protease-sensitivity of the hTERT N-terminus, indicating that a conformational change in this region of hTERT is likely critical for catalytic function.Conclusions/significanceWe provide the first detailed evidence regarding the biochemical and cellular roles of an evolutionarily-conserved Gln residue in higher eukaryotes. Collectively, our results indicate that Q169 is needed to maintain the hTERT N-terminus in a conformation that is necessary for optimal enzyme-primer interactions and nucleotide incorporation. We show that Q169 is critical for the structure and function of human telomerase, thereby identifying a novel residue in hTERT that may be amenable to therapeutic intervention.

Dataset Information

Polymorphisms in human telomerase reverse transcriptase (hTERT) gene, gene- gene and gene-smoking interaction with susceptibility to gastric cancer in Chinese Han population.

Publications

Polymorphisms in human telomerase reverse transcriptase (hTERT) gene, gene- gene and gene-smoking interaction with susceptibility to gastric cancer in Chinese Han population.

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