Telomere and telomerase in oncology

Abstract

Shortening of the telomeric DNA at the chromosome ends is presumed to limit the lifespan of human cells and elicit a signal for the onset of cellular senescence. To continually proliferate across the senescent checkpoint, cells must restore and preserve telomere length. This can be achieved by telomerase, which has the reverse transcriptase activity. Telomerase activity is negative in human normal somatic cells but can be detected in most tumor cells. The enzyme is proposed to be an essential factor in cell immortalization and cancer progression. In this review we discuss the structure and function of telomere and telomerase and their roles in cell immortalization and oncogenesis. Simultaneously the experimental studies of telomerase assays for cancer detection and diagnosis are reviewed. Finally, we discuss the potential use of inhibitors of telomerase in anti-cancer therapy.Key words: Telomere, telomerase, cancer, telomerase assay, inhibitor. REVIEWTelomere and cell replicative senescence Telomeres, which are located at the end of chromosome, are crucial to protect chromosome against degeneration, rearrangment and end to end fusion [1]. Human telomeres are tandemly repeated units of the hexanucleotide TTAGGG. The estimated length of telomeric DNA varies from 2 to 20 kilo base pairs, depending on factors such as tissue type and human age. The buck of telomeric DNA is doublestranded, but the end of telomeric DNA consists of 3' overhang of single-stranded repeats. Sequencespecific DNA-binding proteins (TRF1 and TRF2) attach to the telomeric DNA repeats. These proteins help maintain telomere stability and regulate telomere length [2].Owing to the nature of lagging-strand DNA synthesis, traditional DNA polymerases are unable to completely replicate the ends of linear DNA [3]. Incomplete replication leads to the loss of 50-200 base pairs of the end of telomeric DNA with each round of DNA replication. Hence, the continual cycles of cell growth and division bring on progressing telomere shortening [4]. Now it is clear that telomere shortening is responsible for inducing the senescent phenotype that results from repeated cell division, but the mechanism how a short telomere induces the senescence is still unknown. Possible mechanism includes the short telomere inducing a DNA damage response, releasing transcriptional regulatory factors from sequestration, and relaxing heterochromatin which can lead to the arrest of cell growth and the cell senescence [5]. Senescence represents a state in which cells no longer proliferate but remain viable for extended periods. The cells which are about to enter the senescent state can be induced to bypass senescence through the introduction of viral oncogenes such as SVA40 Large T antigen (LT) and the HPV E6 or E7 protein. These viral proteins can inactivate p53 and Rb tumor suppressor pathways, which play a pivotal role in inducing the senescence phenotype. These cells that bypass senescence state continue to proliferate and suffer from further telomere loss. So the shortening

Retracted: Impact of genomic instability in risk assessment and chemoprevention of oral premalignancies

“…However, telomerase activity is normally found in lymphocytes; and considering that leukoplakias are often associated with chronic inflammation in the submucosa, interpretations of telomerase activity may be confounded. 40,41 Jiang et al 33 analyzed oral leukoplakias with respect to loss of heterozygosity (LOH) and found a high prevalence of LOH in oral leukoplakias and an increase in LOH from leukoplakias to foci of early cancerization. These results notwithstanding, their prognostic impact was not documented.…”

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“…Estas estruturas, compreendem sequências de nucleótidos que protegem as extremidades dos cromossomas da sua degeneração e da fusão com outros cromossomas, prevenindo a instabilidade genómica (22,34,105,123,150,170). Para além destas funções, os telómeros desempenham também um papel importante indirecto no controlo da proliferação das células normais e no crescimento anormal do cancro (81,105,150).…”

“…Para além destas funções, os telómeros desempenham também um papel importante indirecto no controlo da proliferação das células normais e no crescimento anormal do cancro (81,105,150). Na ausência da telomerase, uma enzima que adiciona repetições sucessivas de bases de DNA telomérico aos telómeros, em cada duplicação celular a célula perde entre 50 e 201 pares de bases (bp) de DNA telomérico (105,170). Aparentemente, as células humanas deixam de se dividir quando o comprimento final do DNA telomé-rico atinge aproximadamente 4-7 bp (15 a 20 nas células germinais) prevenindo, assim, a fusão com outros cromossomas (105).…”

Telomere maintenance in childhood primitive neuroectodermal brain tumors

“…They fail to acquire telomerase activity in successive cultures and become senescent. In contrast, telomerase activity has been detected in numerous cancer cells and tissues (Kim et al, 1994;Mu and Wei, 2002).…”

“…They fail to acquire telomerase activity in successive cultures and become senescent. In contrast, telomerase activity has been detected in numerous cancer cells and tissues (Kim et al, 1994;Mu and Wei, 2002).Brain tumors in which telomerase activity has been detected include glioblastoma, anaplastic astrocytoma, oligodendroglioma, and meningioma (Hiraga et al, 1998;Langford et al, 1995;Sano et al, 1998). Increased expression of the telomerase RNA component was found to be associated with increased cell proliferation in astrocytomas and ependymomas (Grosso and Schiffer, 1998).…”