DNA damage - Inhibition of telomerase activity and cellular senescence

Inhibition of telomerase activity and cellular senescence

Telomeres are the physical ends of the chromosomes. They are composed of the repeated sequence TTAGGG and multiple protein components and are responsible for maintaining chromosomal stability and prevent chromosomal end-joining [1], [2], [3]. In chromosomes telomeres serve as stabilizing caps [2]. During the proliferation of mammalian cells, the telomere shortens after every round of DNA replication. Critical telomere shortening or uncapping of telomere binding proteins result in telomere dysfunction initiating DNA damage response signals that contribute to either cellular senescence or apoptosis [4]. Lost sequences of the telomeres at each replication cycle can be resynthesized by telomerase [5]. Telomerase is repressed in normal human somatic cells but is activated during development and upon neoplasia [1], [6], [7], [8]. Repression of telomerase activity contributes to cellular senescence and apoptosis [4], [8], [9].

The human telomerase complex is a ribonucleoprotein containing an integral RNA: Telomerase RNA component (TERC), a Telomerase reverse transcriptase (TERT), and several associated proteins [10].

Telomerase activity can be regulated by transcriptional and post-translational mechanisms. Tumor protein p53 (p53) and Breast cancer 1, early onset (Brca1) inhibit transcription of TERT [11], [12]. In addition, p53 binds and suppresses activity of Telomerase-associated protein 1 (TEP1) leading to inhibition of telomerase complex [7], [13]. p53, Tumor protein p73 (p73) and Cyclin-dependent kinase inhibitor 2A (p16INK4) also bind and inhibit Sp1 transcription factor (SP1) leading to suppression of transcription of TERT [14], [15], [16]. p53 inhibits expression of TERT via induction of transcription of Cyclin-dependent kinase inhibitor 1A (p21) [17]. p21 and p16INK4 bind and inactivate cyclin-dependent kinases 2, 4 and 6 (CDK2, CDK4 and CDK6) leading to activation of Retinoblastoma 1 (Rb protein), Retinoblastoma-like 1 and 2 (p107, p130) that bind and inhibit E2F transcription factor 1 (E2F1) [7], [18]. Inhibition of E2F1 leads to suppression of TERT transcription [14], [18], [19].

Protein phosphatase 2, catalytic subunit (PP2A catalytic) dephosphorylates TEP1, v-akt murine thymoma viral oncogene homologs (AKT(PKB)) and TERT leading to inhibition of telomerase activity [3], [7], [20], [21].

Sjogren syndrome antigen B (La protein) binds and suppresses TERC promoting telomere shortening [22].

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