Telomeres and Cancer

Abstract

Telomeres cap the ends of eukaryotic chromosomes and are indispensable chromatin structures for genome protection and replication. Telomere length maintenance has been attributed to several functional modulators, including telomerase, the shelterin complex, and the CST complex, synergizing with DNA replication, repair, and the RNA metabolism pathway components. As dysfunctional telomere maintenance and telomerase activation are associated with several human diseases, including cancer, the molecular mechanisms behind telomere length regulation and protection need particular emphasis. Cancer cells exhibit telomerase activation, enabling replicative immortality. Telomerase reverse transcriptase (TERT) activation is involved in cancer development through diverse activities other than mediating telomere elongation. This review describes the telomere functions, the role of functional modulators, the implications in cancer development, and the future therapeutic opportunities.

Keywords: CST; promoter mutations; shelterin; telomerase; telomerase reverse transcriptase.

Figure 1

A graphic presentation of telomeric DNA and the proteins that form the shelterin complex. Telomeres are capping structures and are situated at the ends of linear chromosomes. Telomeric DNA, TTAGGG at the chromosome ends, and the complementary DNA strand sequence AATCCC form an extended region of dsDNA ending with a ssDNA G-rich overhang. The 3′ G-rich overhang enables telomeric DNA to form a secondary structure in which the 3′ single-stranded overhang folds back and displaces a strand in the homologous dsDNA TTAGGG region, to create a D-loop that protects the 3′-end from being identified as damaged DNA, thereby preventing the activation of the ataxia-telangiectasia mutation and Rad3-related (ATM/ATR) damage response pathways. The shelterin complex comprises six telomeric proteins: TRF1, TRF2, RAP1, TIN2, POT1, and TPP1. The complex enables the telomeric 3′-overhang/G-tail to fold into a lasso-like structure with a telomeric loop (T-loop) that protects the 3′-end from being recognized for DNA damage and blocks the DNA damage response.

Figure 2

Interaction of the shelterin complex, CST complex and telomerase to maintain telomere length. (A) The shelterin complex is essential for telomere protection and for regulating telomere elongation. TIN2, RAP1, and TRF1/2 subunits of the shelterin complex associate with telomeric dsDNA, while POT1 and TPP1 bind telomeric ssDNA and are responsible for recruiting telomerase to the telomeres. The shelterin complex also stimulates extension of the G-overhang by telomerase. (B) The CST complex prevents telomerase from engaging the G-overhang and facilitates the C-strand fill-in. The CST complex has three components—conserved telomere protection component 1 (CTC1), suppressor of cdc thirteen 1 (STN1) and telomeric pathway with STN1 (TEN1)—which are thought to function in part in telomere lagging-strand synthesis. The human telomerase consists of the hTERT, the TERC, and accessory proteins. The hTERT can wrap the chromosome to add single-stranded telomere repeats. The TERC contains the template for telomere replication. When an ongoing extension of a stranded DNA is finished, telomerase activity is terminated at the ssDNA overhang by the CST complex, which also activates the C-strand fill-in: the CST complex recruits DNA polymerase alpha (Polα) for lagging strand synthesis of the telomeric C-strand to convert the newly synthesized G-overhang into double-stranded DNA.

Figure 3

Comparison of (A) S. cerevisiae Rfa and CST with (B) human RPA and CST. Domain structures of Rfa and CST. DBD: DNA-binding domain;OB: OB-fold domain; RD: recruitment domain; TR2: the single RAD51-binding domain; WH: winged helix domain; wHTH: winged helix-turn-helix domain.

Figure 4

Schematic structure of telomerase. (A)Components of telomerase consist of the TERT (hTERT), the telomerase RNA template (TERC), and accessory proteins, including dyskerin, GAR1, NHP2, and NOP10. HSP 90, p23, pontin, reptin, and serine, SRSF11, and TCAB1. (B) The hTERT gene is situated on 5p15.33 which is responsible for 40 kb of human genome. The hTERT gene promoter contains five GC boxes (5′-GGGCGG-3′), two E-boxes (5′-CACGTG-3′), and one TSS. GC boxes are interacted with SP-1; E-boxes also have binding sites to MAD1; TSS binds THF1. Point mutations at the TERT promoter, predominantly at two points (C228T and C250T) generate new ETS/ternary complex (ETS/TCF) binding sites for transcription factors (TF). Increasing the expression of TFs such as c-MYC, ETS, NF-kB, and SP-1 results in binding to their particular sites and can up-regulate hTERT transcription. Binding of down-regulating transcription factors, such as WT1, CTCF, and MZF2, down-regulate TERT transcription. CTCF: CCCTC-binding factor; hTERT: human telomerase reverse transcriptase; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B; TSS: transcription start site; WT1: Wilms tumor protein1; MZF2: myeloid zinc finger protein 2; GAR1: glycine-arginine rich 1; NHP2: non-histone protein 2; NOP10: nucleolar protein 10; HSP90: heat shock protein 90; TCAB1: telomerase Cajal body protein 1; SRSF11: serine and arginine-rich splicing factor 11.