Dataset Information

In silico analysis of human Telomerase Reverse Transcriptase (hTERT) gene: identification of a distant homolog of Melanoma Antigen Family Gene (MAGE).

ABSTRACT: Melanoma antigen family (MAGE) genes are widely expressed in various tumor types but silent in normal cells except germ-line cells lacking human leukocyte antigen (HLA) expression. Over 25 MAGE genes have been identified in different tissues, mostly located in Xq28 of human chromosome and some of them in chromosome 3 and 15, containing either single or multiple-exons. This in silico study predicted the genes on hTERT location and identified a distant relative of MAGE gene located on chromosome 5. The study identified a single exon coding ~850 residues polypeptide sharing ~30% homology with Macfa-MAGE E1 and hMAGE-E1. dbEST search of the predicted transcript matches 5' and 3' flanking ESTs. The predicted protein showed sequence homology within the MAGE homology domain 2 (MHD2). UCSC genome annotation of CpG Island around the coding region reveals that this gene could be silent by methylation. Affymetrix all-exon track indicates the gene could be expressed in different tissues particularly in cancer cells as they widely undergo a genome wide demethylation process.

SUBMITTER: Amin R

PROVIDER: S-EPMC2791492 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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In silico analysis of human Telomerase Reverse Transcriptase (hTERT) gene: identification of a distant homolog of Melanoma Antigen Family Gene (MAGE).

Amin Ruhul R Jesmin Jamil Hasan H Hossain M Anwar MA

Cancer informatics 20091124

Melanoma antigen family (MAGE) genes are widely expressed in various tumor types but silent in normal cells except germ-line cells lacking human leukocyte antigen (HLA) expression. Over 25 MAGE genes have been identified in different tissues, mostly located in Xq28 of human chromosome and some of them in chromosome 3 and 15, containing either single or multiple-exons. This in silico study predicted the genes on hTERT location and identified a distant relative of MAGE gene located on chromosome 5 ...[more]

PMID: 20011463

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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

In silico analysis of human Telomerase Reverse Transcriptase (hTERT) gene: identification of a distant homolog of Melanoma Antigen Family Gene (MAGE).

Publications

In silico analysis of human Telomerase Reverse Transcriptase (hTERT) gene: identification of a distant homolog of Melanoma Antigen Family Gene (MAGE).

Similar Datasets

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