Journal of Genetic Disorders & Genetic Reports ISSN: 2327-5790

All submissions of the EM system will be redirected to Online Manuscript Submission System. Authors are requested to submit articles directly to Online Manuscript Submission System of respective journal.

Review Article, J Genet Disor Genet Rep Vol: 5 Issue: 1

Telomeres in Cancer: Length, Positioning and Epigenetics

Patel TN*, Sulekha R Nair, Lekshmi Mohan, Fahmina Y, Ashwini Devi S and VA Saimadhukiran Dabbiru
Division of Medical Biotechnology, SBST, VIT, Vellore 632014, Tamilnadu, India
Corresponding author : TN Patel, Associate Professor
Division of Medical Biotechnology, SBST, VIT, Vellore-632014, Tamilnadu, India
Tel: 9597873669
E-mail: [email protected]
Received: November 03, 2015 Accepted: January 21, 2016 Published: January 27, 2016
Citation: Patel TN, Nair SR, Mohan L, Fahmina Y, AshwiniDevi S, et al. (2016) Telomeres in Cancer: Length, Positioning and Epigenetics. J Genet Disor Genet Rep 5:1. doi:10.4172/2327-5790.1000131


Telomeres, the tandem nucleotide sequences at the termini of the DNA, enables the masking of DNA from repair mechanisms, thus protecting them from being considered as double stranded breaks. When the maintenance of telomeres goes awry, several diseases including cancer are resulted. Here in this review, we give an account of how telomere shortening, lengthening, positioning in the nucleus and its associated epigenetic modifications set cancer cells apart from normal cells.

Keywords: Telomere; Telomerase; ALT; BFB cycles; Lamin A/C; HMTases; Epigenesis; Chromatin remodelers


Telomere; Telomerase; ALT; BFB cycles; Lamin A/C; HMTases; Epigenesis; Chromatin remodelers


Telomeres are short stretch of repetitive sequences at the termini of chromosomes which have been reported in a wide variety of organisms ranging from prokaryotes like Borrelia burgdorferi to all higher eukaryotes. In humans, telomeres occur as TTAGGG repeats forming t loop and D loop at the chromosomal termini [1]. A protein complex called shelterin, associate and stabilise telomeres through repression of ATM and ATR kinase signalling pathways thereby precluding the non-homologous end joining (NHEJ) and homology directed repair pathways (HDR) [2-4]. Dissociation of shelterin complex or its associated factors ultimately leads to senescence or cellular apoptosis by, different mechanisms including Non- Homologous End Joining (NHEJ), homologous recombination (HR) associated repair [4-7].
The function of the telomeres is to act as disposable buffers at the ends of chromosomes which are truncated during replication (due to end-replication problem) [8]. Thus, due to their significance in protecting the genes at the subtelomeric positions from being truncated, negating the telomere position effect, as well as their pivotal role in preventing fusion of chromosomal ends and recombination due to capping function, telomere maintenance is essential during cellular life cycle [8]. However, telomere mis-maintenance is of greater significance in manifestation of many diseases, grouped under telomeropathies which include cancer, human syndrome ataxia telangiectasia, heart disease, ulcerative colitis, liver cirrhosis, atheroscelorosis, dyskeratosis congenita (DC), Fanconi anaemia and aplastic anaemia [8]. While accelerated telomere shortening is a part of premature aging in DC, it is significant in cancerous cells as well, wherein each cell division is accompanied by telomere shortening and replenishing by telomerase activation or by mechanisms of alternative lengthening of telomeres (ALT) [8,9].
The 3D genome organization in a cancer interphase nucleus differ due to multiple chromosomal distortions leading to altered gene expression [10,11]. The 3D organisation of the telomere in a tumor cell may develop as aggregate unlike their scattered distribution in the normal cells which form clusters which vary in their sizes depending on telomere-telomere fusion and formation of dicentrics [10].
In this review, we discuss how different attributes of telomeres – their length, position and epigenetics are distinct in normal healthy cells and how their alterations promote carcinogenesis.

Telomere Length

In normal cells
Telomere length is carefully regulated in normal cells so that they may achieve replicative senescence and therefore, remain mortal [12]. Double-stranded telomere is bound by two important sequencespecific DNA binding proteins – telomeric repeat binding factor 1 (TRF1) and telomeric repeat binding factor 2 (TRF2), of which TRF1 has the specific function to modulate telomere length while also serving to facilitate DNA replication through the telomere repeats (which acts as fragile DNA sites) while TRF2 is responsible for protective capping of chromosomal end and for preventing chromosomal end ligation [13]. Both of these proteins interact with TRF1-interacting nuclear factor (TIN2) to nucleate the shelterin complex that contains an important subunit called the protection of telomeres 1 (POT1) [4]. This POT1 protein is instrumental in the capping of single-stranded telomeric portion and controlling of telomerase action by inhibiting it at telomeric end [14]. All these actions result in the maintenance of telomeres and telomeric length in normal cells with progressive shortening of telomere with each cell division until a point when the telomere can no longer become shorter [13]. This point signals the cell to undergo replicative senescence that finally contributes to cellular aging and apoptosis [15]. This point is called the Hayflick Limit named after Leonard Hayflick who discovered that cultured normal human cells have a limited capacity to divide, after which they stop growing, become enlarged, engaging a new pathway termed replicative senescence [16,17]. Loss of these controls along with high expression of telomerase results in the maintenance of telomere length that allows the cell to divide indefinitely and turn cancerous. Telomere restriction fragment (TRF) analysis is one of the traditional methods used to study the telomere length in vitro. However, quantitative real time PCR based method for absolute telomere length estimation has been developed and currently being used in cancer research [18].
Telomere shortening
It is known that telomere shortening plays a critical role in cellular aging and replicative senescence [19]. Telomere shortening is a major implication of end replication problem encountered during DNA replication [19]. After repeated cycles of cell divisions, dysfunctional telomeres (shortened telomeres) arise and induce senescence by p53 which when evaded, the cells continue to divide and the telomere length is critically shortened enabling the recruitment of DNA repair machinery and rectifying the recognised double stranded breaks [13]. This happens due to dissociation of TRF2 of shelterin complex from dysfunctional telomeres stimulating the activation of DNA Damage Response (DDR) involving molecules like γH2AX, 53BP1, RAD17, ATM, Mre11 and forming “telomere dysfunction induced foci”, ultimately leading to activation of ATM Kinase and repair of double stranded breaks [13,20]. It results in the hazardous consequence of telomere repair and maintenance instigating aberrant cell survival. Along with this loss of components of DDR involving molecules or the molecules which interact with DDR components increase the risk of cancer through evasion of apoptosis and induction of Breakage-Fusion-Bridge cycles(BFB cycles) [21]. BFB cycles results in mutations such as deletion, gene manipulation, translocation and other chromosomal anomalies associated with tumorigenesis [22-24]. Several other factors also induce BFB cycles- for instance, breakage at chromosomal fragility sites instigating cancer initiation and progression [25].
Telomere shortening and micro RNAs: miRNA microarray analysis in SK-N-MC(Ewing Sarcoma) cells with shortened telomeres revealed upregulation of miRNAs- miR- 199a and miR-Let7a-d, involved in apoptotic or growth suppression. [26]. Telomere shortening alters the expression of various other significant miRNAs and a complete profile of mis-regulated miRNAs and proteins associated with telomere shortening, highlights the possible target genes and miRNAs in telomere shortening associated cancer progression [27,28]. Interestingly, a recent report unveiled the role of miRNA in shelterin complex integrity and telomere fragility. In human breast cancer cells, miR-155 over-expression is related to down regulation of TRF1 of shelterin complex promoting telomere fragility and shortening [29]. Further insights in this aspect of telomere research might deconvolute the role of several “telo-miRNAs” in cancer.
Telomere lengthening
In human cancer cells, cellular senescence and DNA damage signalling pathways are almost universally bypassed by abrogating important cell cycle checkpoint genes leading to extended growth of the pre-malignant cells eventually reaching the crisis stage [30]. Crisis is a period where cell growth and death are in balance. Due to chromosome end fusions, there are chromosome breakage-fusionbridge events, genomic instability, rearrangements of chromosomes, and eventually engagement of telomerase [15]. Once a cell undergoes initial carcinogenic changes, the telomere lengthening becomes inevitable. The extended cell growth and proliferation of a committed cancer cell is supported by activation of enzyme telomerase or through ALT mechanism.
Telomerase-dependent telomere lengthening: Telomerase is a reverse transcriptase enzyme that includes the TERT catalytic subunit and RNA component (TERC) which mediates maintenance of telomere length in stem cells and reproductive cells [31]. By default, telomerase activity is minimal in all normal healthy cells except the germ cells [31]. Telomerase activation is found in cancer cells multifold above detectable limits, which regulates the telomere length and causes faulty telomere maintenance leading to major implications in cancer progression [9]. Telomere Repeat Amplification Protocol (TRAP) and various modifications of this assay have been developed successfully to study up-regulation of telomerase activity in immortal cells [32].
Telomerase trafficking in the cancer cell is mediated by TERT and TERC subunits wherein TERC functions as the template for the enzyme to add telomere repeats in a reverse transcriptase reaction at the chromosome end while TERT catalyzes the reaction [13]. This process also requires additional proteins such as dyskerin, H/ ACA (motif sequence) snoRNAs (small nucleolar RNAs), scaRNAs (small Cajal body-specific RNAs) and telomerase Cajal body protein 1 (TCAB1), that are stable components of the holoenzyme, for proper assembly, trafficking and function in human cancer cells [33].
At present, certain queries to telomerae regulation remains unclear viz., to what extent the other components of the telomerase holoenzyme are regulated, how assembly of telomerase is controlled, whether and how post translational modifications impact on enzyme access and activity and finally how many other pathways impinge on control of TERT protein [13].
ALT mechanism: Another mechanism of telomere length maintenance is the ALT (Alternative lengthening of telomeres) pathway that drives telomere elongation via homologous recombination (HR) with other telomeres or extra-chromosomal repeats and is employed in 10-15% of “telomerase negative cancers” and in sarcomas of complicated karyotypes [9]. The ALT positive cancer cells are characterized by very long heterogeneous telomere DNA, the presence of extra-chromosomal repeats, extensive genomic instability and DNA damage signalling, and deficient G2/M checkpoint of the cell cycle [34]. ALT positive cancer cells are also known to associate with promyelocytic leukemia (PML) bodies – the dynamic nuclear structures involved in many cellular processes, especially in post translational modification of the proteins [35]. Such PML bodies constitute shelterin complex proteins, telomeric DNA and homologous recombination (HR) factors including Mre11- Rad50-Nbs1 (MRN) complex which are termed as ALT associated PML bodies or APBs [36,37]. These APBs are recruited when ALT is activated in a cell and repressed when ALT is inactivated [38].
The ALT telomeres are seen to contain abundant amount of abnormal DNA sequences, where, first, they produce many C-circle products with deoxy Cytidine TriPhosphate (dCTP) in the presence of sequences other than TTAGGG [39], i.e., it produces partially specific telomeric (CCCTAA)n sequence which is highly ALT specific implying that they are produced when ALT is activated in the cells. This c-circle supports the formation of abnormal protein products, which is detected by the c-circle assay [38]. Secondly, ALT telomere cells are able to produce large amount of non-telomeric sequence such as SV40 DNA– a gene that suppresses the tumor suppressor protein p53 leading to cell proliferation and aids tumour development as shown by Conomos and co-researchers [40,41]. From their study, it was observed that human telomerase positive cells show negative correlation of subtelomeric DNA methylation with telomere length and recombination. While treatment with demethylating agents, the level of subtelomeric DNA methylation is seen to be heterogeneous in human ALT cells. Another characteristic of the ALT cells is related to chromatin remodelling wherein remodeler proteins are seen in ALT cells but not in telomerase positive cells [40,42]. Various nuclear receptors binding to variant repeats and expressing their genes are a unique property of the ALT cells [43,44]. Such activation may change the heterochromatic condition of the ALT telomeres and further more help in de-repression of telomeric recombination [40].

Telomere Positioning

Telomere positioning is an important feature of studying not only the movement and function of telomeres but also the proximity of different chromosomes with each other. Telomere positioning and organisation in the nucleus is defined by certain important parameters:
1) The number of telomeres
2) Telomere length
3) Distance of each telomere from the nuclear centre versus the periphery
4) Shelterin complex integrity
5) Association of telomeres with nuclear matrix
One of the approaches to study the structure and organization of genome in a nucleus is by fluorescently labelling the telomeres and measuring their 3D organization. The data obtained by the 3D fluorescent measurements is then analysed by a programme called TeloviewTM which helps to find all the telomeres in a nucleus including their shape, size as well as organization [45]. By this method, the telomeres separated by merely 20nm can be precisely distinguished. It is expected to observe 92 telomeres in a normal human somatic cell but usually able to identify only around 50, [10,46,47] probably because the telomeres are closer than the optical resolution. Interestingly, Teloview data suggested that telomeres exhibit a distinct geometry within the nucleus, implicitly understating the chromosome dynamics and their alterations both in normal and cancer cells.
In normal cell
In the 3D nucleus of a normal cell, the telomere positions are not static and seem to exhibit species specificity [46,48,49]. Telomeres are organised in a very typical way within the interphase nucleus and can also move at varying distances [46]. Normal lymphocytes of mouse or human origin show a cell cycle-dependent organization of telomeres in their interphase nuclei [10,48]. However, the mechanisms of telomere positions have been well elucidated in mouse lymphocytes in different cell cycle stages [10]. Under optimal growth conditions, in an unperturbed nucleus of normal G0/G1 cells, telomeres exhibit a distinct sphere shape indicating their wide distribution throughout the nucleus [10]. S-phase cells display a similar pattern of telomere organization and, in addition, show replicative structures of telomeres [10,45,46]. The overall nuclear distribution of telomeres change as the cycle enters G2 phase. The telomeres align themselves along the centre of the optical axis (z axis) in the nucleus of cell. This can be visualised as a distinct disk shape indicating the concentration of telomeres at the centre of the nucleus [10].
In cancer cells
Telomere aggregates are the major signal to genomic instability and observed mainly due to overlapping of the telomeres in interphase nuclei. This can lead to BFB cycles and other chromosomal distortions which ultimately direct to cancer development and promotion. [49]. Various cancer cell lines viz., Burkitt Lymphoma cell line, Colon carcinoma cell lines, primary mouse plasmocytoma cells, primary human head and neck squamous cell carcinoma stage IV cells and human neuroblastoma cell lines when observed in TeloviewTM after 3D FISH, suggest that the telomere disk in the G2 phase displayed a distorted shape- higher in volume [10]. Telomere dynamics is accelerated by down-regulation of shelterin complex proteins in Epstein barr virus positive Hodgkin’s lymphoma suggesting the role of shelterin complex in regulating movement of chromosomes via telomeres [50]. Similarly, non-random chromosome positioning or altered chromosome positions within cells at initial stages of carcinogenesis allow them to “grope” each other and induce translocation events [51,52].
C-Myc, one of the important proteins mis-regulated in 70% of cancers has also been reported to switch on the nuclear remodelling – both in altering chromosome positioning and inducing genomic instability [52]. In pre-B lymphocyte cells where C-Myc is deregulated, the chromosome pairs 5 and 13, 17 and 7, 7 and 10 alter their positions and come to close proximity to each other, a prerequisite condition for translocation between the above said chromosome pairs [52]. C-Myc deregulation also initiates BFB cycles through end to end chromosome fusions. Further propagation continues until no more telomere end is available for fusion with other chromosomes, thus leading to genomic instability [52]. Telomere aggregates are usually seen in c-myc deregulated cells enhancing the proliferative pathways and thus contributing to explosion of cells with damaged DNA resulting into genomic instability by aneuploidy or translocations [53]. In plasmacytoma, a condition in mice, 12 and 15 chromosomes in B-cells come to close vicinity to result in a translocation. In human chronic myeloid leukaemia, positioning of 9 and 22 chromosomes enables translocation [52,54].
This proximity of various chromosome regions and aggregations of telomere in nucleus of cancer cell in three dimensions emphasize genome distortion and chromatin remodelling during cancer. It is well suggested and now in progress to use three dimensional (3D) telomere dynamics as a tool for diagnosing cancer at early stages [55].
Nuclear matrix and telomeres positioning
The role of nuclear matrix in chromosome distribution and telomere association restrictions in a normal cell is worth noting. Several reports suggested that telomeres are tethered to nuclear matrix, thus constraining its movement within the nucleus [56]. TIN2L, an isoform of TIN2 of shelterin complex works in association with the nuclear matrix and thus limits telomeric regions of DNA to nuclear matrix [57]. Tethering of telomeres to nuclear lamina is also dependent on Lamin proteins that form intermediate filaments in nucleus. Lamin A and Lamin C, splice variants of LMNA gene are one of the classes of Lamins which contribute to telomere territory confinements in the normal cells. Decrease in Lamin A/C and Emerin (a protein which interacts with nuclear lamins and actin tubules within nucleus) stimulates the movement of telomeres within the cell nucleus [58]. Loss of Lamin A or alterations induced during cancer is directly linked to increased genomic instability through destabilization of DDR component 53BP1 [59]. Furthermore, mis-expression of certain lamins may be linked to commitment of cancer cells towards metastasis through dynamism of chromatin [60]. Recent evidences have supported that the cytoskeleton transformation during genesis of cancer results in mechanical forces that transmit through the nuclear envelope, nuclear lamina and regulate telomere dynamics [61].

Telomere Epigenetic Modifications

Telomeres belong to constitutive heterochromatin, and their regulation and epigenetic modification are of great interest in order to achieve breakthrough in understanding and drawing solutions to many medical problems such as cancers and ageing [62]. Epigenetic modifications such as methylation and acetylation marks are mediated by various proteins and chromatin remodelers discussed in detail as follows.
Normal telomere epigenetic modifications
As pointed out earlier in this article, the protection of chromosome ends from DNA repair and other degradation activities is mediated by specialized protein complexes called shelterin, bound to telomere repeats. It has become apparent that epigenetic regulation of the telomeric chromatin template critically impacts telomere function and telomere-length homeostasis in several organisms ranging from yeast to human [34,63]. The current discoveries of telomere chromatin regulation during early mammalian development, as well as during nuclear reprogramming of various cellular processes, further highlight a central role of telomere chromatin. In addition, telomere sequences were recently shown to generate long, non-coding RNAs that remain associated to telomeric chromatin and provide newer insights into the regulation of telomeres [64]. Telomeres are bound by nucleosome arrays that are characteristic to constitutive heterochromatin and are found to be subjected to various epigenetic modifications such as methylation and acetylation [65].
In literature, a heterochromatic mark refers to any epigenetic modification in a region of DNA strand which makes that particular region of DNA sequence to be compact and “untranscriptable”, i.e., makes the sequence heterochromatic [8,65]. Heterochromatic marks at telomeres have been proposed to act as negative regulators of telomere elongation [65]. In normal cells, telomeres are similar to pericentric heterochromatin in that they are enriched for binding of HP1 (Heterochromatin protein 1) isoforms: HP1α, HP1β and HP1γ via the H3K9 and H4K20 (tri-methylated histone 3 at lysine 9 and trimethylated histone 4 at lysine 20) modifications that are carried out by the HMTases (Histone Methyl Transferases) – SUV39H (suppressor of variegation 3-9 homologue) and SUV4-20H, respectively [65,66]. In addition to these histone heterochromatic marks, telomeric repeats are also seen to contain di-methylated H3K79, mediated by the Dot1L HMTase [67]. Dot1L protein plays a major role in meiotic checkpoint control [68] and is also important for the di-methylation of H3K9, acting in association with additional H3K9-specific HMTases, such as G9a or ESET (ERG-associated protein with SET domain) [67].
Loss of these histone heterochromatic marks and/or HP1 results in substantial telomere elongation [65] and impairs heterochromatin and genome stability [69] while loss of DNA heterochromatic marks in the subtelomeric regions due to loss of DNMT1 (DNA Methyl Transferase 1), DNMT3ab and Dicer proteins results in dramatic telomere elongation, which are accompanied by increased abundance of histone heterochromatic marks at telomeric repeats [70]. Several studies corroborate this [71-78] and prove that H3K9 methylation is essential for creating binding sites for HP1 proteins [74], thereby epigenetically controlling heterochromatin assembly [75]; SUV4-20H deficiency leads to telomere elongation and derepression of telomeric recombination due to a switch to monomethylation of H4K20 [76,77]; while DNMTs control telomere length and recombination, especially in mammalian cells [78]. Therefore, in either case of loss of DNA or histone heterochromatic marks, the telomere recombination frequencies are higher, suggesting that the normal function of repressive marks at telomeric and subtelomeric chromatin is to repress recombination events [65,70] and prevent telomeric instability. Thus, di/tri-methylation of H3K9, trimethylation of H4K20 and trimethylation of H3K79 via HP1, and methylation of subtelomeric DNA are collectively called Repressive heterochromatic marks [65]. In addition to the repressive heterochromatic marks, histones 3 and 4 are also under-acetylated. The HDAC (Histone Deacetylase protein), SIRT6 (human homolog of sirtuin 6 protein) ensures that H3K9 remains under-acetylated and thus, prevents telomere dysfunction [79]. Thus, together, appropriate levels of methylation and acetylation at heterochromatic marks mediate normal telomere function and stability.
In cancer, these markers or rather, their lack thereof, are highly specific: loss or alteration of the Repressive heterochromatic marks of DNA methylation, H4K20me3, and Suv4-20h and Suv39h HMTases lead to tumorigenesis in humans [64] while loss of H3K9me2 and H3K9me3 leads to increased incidence of B-cell lymphoma [8]. In paediatric cancers, the common mutations are on the H3.3 histone variants at K27, G34 and K36 [80] of which mutation at G34 leads to hypomethylation of DNA in telomeric region that leads to ‘open’ configuration of telomeres and subsequent telomere dysfunction and cancer [81].
Another important telomeric mark is the tri-methylation of H4K20 mediated by the retinoblastoma protein (pRb) along with the chromatin remodelling ‘writers’ - SUV39H1 and SUV39H2 HMTases [82]. Loss of this histone heterochromatic mark due to lack of pRb (in various cancers) results in lack of segregation during cell division and loss of telomere length control [70]. Rb protein is frequently mutated in human cancers that results in the loss of H4K20me3 [83] as mentioned previously. Additionally, pRb is also necessary to direct methylation of histone H3, and is necessary for binding of HP1 protein to cyclin E promoter, indicating that the SUV39H1-HP1 complex is involved in heterochromatic silencing, repression of euchromatic genes by Rb and perhaps other co-repressor proteins [84]. Thus, Rbfamily proteins appear to play an important role in both chromosome segregation and telomere-length control, in addition to its more established role in controlling proliferation [70,85]. The absence of SUV39H1 and SUV39H2 in the cell has several adverse consequences including chromosomal mis-segregation, abnormally long telomeres, significant reduction of di- and tri-methylation of H3K9, and, the loss of HP1 binding at telomeres [82]. Although, SUV39H1 has an additional function of preventing Ras-induced tumorigenesis by promoting senescence [86], its role in human cancer is not defined because there have not been any SUV39H1 mutations or losses reported in human cancers [82].
Common chromatin remodelers that localize to the telomeres are: INO80, Ies3 (INO Eighty Subunit 3), and Arp4 (Actin-related Protein 4) [87]. The two main chromatin remodelers that regulate telomere length are INO80 (a DNA helicase and chromatin remodeler) and SWR1 (Swi/Snf2-related 1, homologus to INO80) proteins [87]. Both have been identified in genetic screens for proteins that regulate telomere length [88]. Of these, the Ies3p subunit of the INO80 chromatin remodeling complex interacts with a conserved tetra-trico- peptide-repeat domain of the telomerase protein Est1p [87,88]. Deletion of Ies3 induces telomere elongation and altered telomere position effect while also resulting in heightened levels of telomeretelomere fusions in telomerase-deficient cells [88] suggesting that in the telomerase-positive cells the protein gets over-expressed, or activated, leading to immortalization of the cell.
Telomere epigenetics specific to cancer
ALT pathway is entailed in some of the “telomerase negative cancers”. However, mechanisms to control this pathway have been poorly studied [15]. So far, epigenetic modifications leading to loss of the repressive heterochromatic marks have shown to lead to a derepression of telomere chromatin and exposing it to various proteins of DNA repair and transcriptional factors [13]. The telomeres in these cells, thus, have a more ‘open’ chromatin configuration, which would make them prone to telomere DNA recombination mediated by sister chromatid exchange [13,15]. Therefore, the ‘closed’ or repressive heterochromatic nature of telomere chromatin is necessary to repress ALT activation [8,65]. The most common of such an epigenetic modification leading to loss of repressive marks is caused due to inactivation of ATRX (Alpha Thalassemia Retardation syndrome X-linked protein) gene or dysfunctional ATRX protein [89], although the exact mechanism of these defects on ALT pathway remains unclear [90]. Normally, the ATRX protein acts in complex with DAXX (Death-domain Associated protein 6) as a molecular chaperone to deposit histone variant H3.3 at telomeres so as to ensure that the ALT pathway remains inactivated [90]. However, a single dominant mutation of ATRX gene is insufficient to activate ALT [91] and currently, research is being done to identify all the players necessary to activate the ALT pathway in human cells [81,90-92]. The main types of tumours that are affected by this mechanism include pancreatic neuro-endocrine tumours, neuroblastomas, paediatric glioblastomas, oligodendrogliomas and medulloblastomas [81,91,92].
Telomerase enzyme also could be subjected to epigenetic modification to trigger telomeric dysfunction. Telomerase is expressed by the hTERT gene whose promoter has high epigenetic plasticity that controls its activity [93]. The telomerase promoter has high GC content, suggesting that it is regulated by DNA methylation and in normal conditions, the action of DNMTs on the CpG islands of the promoter results in gene silencing, along with regulation of telomerase activity via histone modification marks [93,94]. Hypermethylation of hTERT promoter plays a critical role in the negative regulation of telomerase activity in oral cancers [95]. Telomerase also shows abnormal histone modifications by the action of HDACs such as Trichostatin A that induces hTERT transcription and enhances telomerase activity [96,97], resulting in lengthening of telomeres and cancer.
All the above possible mechanisms suggest that telomeres suffer epigenetic alterations during tumorigenesis, which in turn are important drivers of telomere length alterations in cancer cells. These epigenetic alterations are also expected to impact on the telomeric chromatin structure, increasing telomere maintenance by ALT or providing improved access for telomerase to the G-strand overhang [65].
It is not known, however, whether increasing telomere compaction can affect the proliferative potential of cancer cells and impact on telomere homeostasis during aging [64].


Telomeres are very important to maintain genomic stability. Mis-maintenance of different telomeric aspects explained in the article confirms the mechanisms by which a normal cell succumbs to cancerous origin. Certain epigenetic modifications are seen to regulate telomeric length, while in some curious cases, telomeric length is seen to regulate certain epigenetic modifications of the cell that allows the system to ‘age’. This complex “checks-and-balances” system on telomeres is what allows the cell to divide and achieve apoptosis and senescence on reaching a certain critical telomeric length and retain the health of tissue or organism. Adverse effects of certain carcinogens or mutagens cause the cell to lose control over its telomere length, resulting in telomere shortening or lengthening (depending on pathway influenced), change in telomere position, telomeric instability, and loss of telomeric compaction which all lead to genomic instability. Thus, cells become uncontrolled, leading to cancer and other old-age degenerative diseases. In addition to studying telomere length and associated pathways resulting in cancer and other aging symptoms in the cell, telomere positioning studies can be done to understand the physical aspects of abnormal telomere function, which may prove to be extremely helpful in discovering potential diagnostic and prognostic tools in the case of such diseases in the future.


Track Your Manuscript

Media Partners