Regulation of telomere length and cellular
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 , , . In chromosomes telomeres serve as stabilizing caps . During the proliferation of mammalian cells, the telomere shortens after every
round of DNA replication . 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 , , , , . Because the lost
sequences of the telomeres at each replication cycle can be resynthesized by telomerase,
the enzyme has essential functions for cellular immortalization , .
The human telomerase complex is a ribonucleoprotein containing an integral RNA:
Telomerase RNA component (TERC), a Telomerase reverse
transcriptase (TERT), and several associated proteins .
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 , , , , , , . Heterogeneous
nuclear ribonucleoprotein A1 (hnRNP A1) associates with
Telomeric DNA and hnRNP C and
stimulates telomerase activity , .
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
, , , . Protein kinase C, alpha
(PKC-alpha) stimulates telomerase activity by
phosphorylation of TERT-associated
TEP1 and by direct phosphorylation of TERT
, . 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 , , .
Telomere binding proteins affects telomere maintenance by modulating the activity of
telomerase , . 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 , , , , , .
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),
TRF1-interacting ankyrin-related ADP-ribose polymerase (Tankyrase
2) and PIN2/TERF1 interacting, telomerase inhibitor 1
(PINX1) , , , , . TIN2
suppresses Tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase
(Tankyrase 1) - mediated
poly(ADP-ribos)ylation of TRF1 thereby activating
TRF1 , , , , . The latter promotes
PINX1 localization in telomeres, and
PINX1 enhances TRF1 interaction
with Telomeric DNA .
PINX1 binds both TERT and
TERC and inhibits telomerase activity thereby promoting
maintenance of telomere length , , , .
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 , , , , , , , , , .
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