Development - Regulation of telomere length and cellular immortalization

Regulation of telomere length and cellular immortalization

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 [4]. Telomerase, a specialized RNA-directed DNA polymerase that extends telomeres of eukaryotic chromosomes, is repressed in normal human somatic cells but is activated during development and upon neoplasia [1], [5], [6], [7], [8]. Because the lost sequences of the telomeres at each replication cycle can be resynthesized by telomerase, the enzyme has essential functions for cellular immortalization [1], [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-associated protein 1 (TEP1), Heat shock protein 90kDa (HSP90), Prostaglandin E synthase 3 (p23 co-chaperone), DKC1 dyskeratosis congenita 1, dyskerin (Dyskerin) (NAP57)), Staufen, RNA binding protein, homolog 1 (Staufen), Heterogeneous nuclear ribonucleoprotein C (hnRNPC), Ribosomal protein L22 (RPL22), X-ray repair complementing defective repair in Chinese hamster cells 6/ 5 (Ku70/80) interact with TERC and TERT and are associated with telomerase activity [6], [11], [12], [13], [14], [15], [16]. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) associates with Telomeric DNA and hnRNP C and stimulates telomerase activity [17], [18].

Telomerase activity can be regulated by transcriptional and post-translational mechanisms. v-myc myelocytomatosis viral oncogene homolog (c-Myc), MYC associated factor X (Max), Sp1 transcription factor (SP1) and E2F transcription factor 1 (E2F1) activate transcription of TERT [19], [6], [20], [21]. Protein kinase C, alpha (PKC-alpha) stimulates telomerase activity by phosphorylation of TERT-associated TEP1 and by direct phosphorylation of TERT [22], [23]. Activation of Phosphoinositide-3-kinase, catalytic (PI3K cat class IA)/ v-akt murine thymoma viral oncogene homologs (AKT(PKB)) pathway leads to AKT(PKB) association with HSP90 and subsequent phosphorylation of TERT promoting activation of telomerase and telomere elongation [3], [23], [24].

Telomere binding proteins affects telomere maintenance by modulating the activity of telomerase [2], [9]. Telomeric repeat binding factors 1 and 2 (TRF1 and TRF2) associate with Telomeric DNA and have an essential role in regulation of telomerase activity and protection and maintenance of telomere ends [4], [25], [26], [27], [28], [29]. TRF1 can control telomerase access through its interaction with TERF1 (TRF1)-interacting nuclear factor 2 (TIN2), Adrenocortical dysplasia homolog (PTOP), Protection of telomeres 1 homolog (POT1), Ku80, Tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase (Tankyrase 2) and PIN2/TERF1 interacting, telomerase inhibitor 1 (PINX1) [2], [14], [15], [26], [29]. TIN2 suppresses Tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase (Tankyrase 1) - mediated poly(ADP-ribos)ylation of TRF1 thereby activating TRF1 [30], [31], [32], [33], [34]. The latter promotes PINX1 localization in telomeres, and PINX1 enhances TRF1 interaction with Telomeric DNA [35]. PINX1 binds both TERT and TERC and inhibits telomerase activity thereby promoting maintenance of telomere length [15], [36], [37], [38].

TRF2 in association with Telomeric repeat binding factor 2, interacting protein (hRap1), MRN complex, POT1 and PTOP inhibits telomerase activity leading to telomere length stabilization thereby promoting cellular immortalization [2], [4], [15], [26], [28], [29], [39], [40], [41], [42].

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