Telomerase regulation at the crossroads of cell fate

Abstract

Telomeres are specialized structures at the ends of eukaryotic chromosomes and are crucial for genome stability, cell growth control and carcinogenesis. Normally, they protect chromosomes from end to end fusion, degradation and recombination. Telomerase is a ribonucleoprotein essential for maintenance of telomeres and it is active in germ cells, stem cells and ∼90% of cancers but not in most normal somatic cells. Human telomerase catalytic protein subunit hTERT is crucial for telomerase activity. Although hTERT expression is sufficient to immortalize normal human cells in culture, spontaneous immortalization is extremely rare which suggests that its expression is under strong negative control. Characterization of the hTERT promoter has allowed for the analysis of potential mechanisms of hTERT expression and regulation. The hTERT promoter is very complex and contains a great number of canonical and non-canonical sequences that bind or potentially bind a variety of transcription factors. In this review we focus on the positive and negative regulators of hTERT transcription and their role in normal cell growth and immortalization.

TERT biology and function in cancer: beyond immortalisation

“…Human TERT gene is located on chromosome 5p15.33 (Cong et al 1999, Bryce et al 2000, spanning 16 exons and 40 kb (Cukusic et al 2008). The TERT promoter region is considered the most important regulatory element for telomerase expression (Cukusic et al 2008).…”

“…The TERT promoter region is considered the most important regulatory element for telomerase expression (Cukusic et al 2008). It spans 330 bp upstream of the translational start site and 37 bp of exon 2 (Cong et al 1999, Cukusic et al 2008, where the 181 bp fragment upstream of the transcriptional start site is the core functional promoter essential for transcriptional activation of TERT in cancer cells (Takakura et al 1999). The promoter region is rich in CpG dinucleotides and SP1 sites, lacking both TATA and CAAT boxes (Takakura et al 1999).…”

“…The promoter region is rich in CpG dinucleotides and SP1 sites, lacking both TATA and CAAT boxes (Takakura et al 1999). This 5′ regulatory region is known to be enriched with transcriptional-binding sites/consensus that interact with both negative and positive regulators of TERT (Renaud et al 2005, Cukusic et al 2008, indicating a high level of regulation by multiple factors (Cong et al 1999) at transcriptional level (Cifuentes-Rojas & Shippen 2012).…”

“…Differential upregulation of TERT activity has been described in cancer cells due to several processes, including transcriptional regulation, alternate RNA splicing and post-translational modifications such as protein phosphorylation (Cong et al 2002, Cukusic et al 2008.…”

Effect of plasmid-mediated RNA interference targeting telomerase reverse transcriptase on lung cancer cells

“…As the catalytic subunit of telomerase, hTERT is highly expressed in telomerase-positive tumor tissues and catalyzes the rate-limiting step in telomerase activation, leading to carcinogenesis (12)(13)(14). Overexpression of hTERT can result in cell immortalization.…”