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Telomeres and disease.

Lansdorp PM - EMBO J. (2009)

Bottom Line: Complete loss of telomerase is tolerated for several generations in most species, but modestly reduced telomerase levels in human beings are implicated in bone marrow failure, pulmonary fibrosis and a spectrum of other diseases including cancer.Here, the crucial role of telomeres and telomerase in human (stem cell) biology is discussed from a Darwinian perspective.It is proposed that the variable phenotype and penetrance of heritable human telomerase deficiencies result from additional environmental, genetic and stochastic factors or combinations thereof.

View Article: PubMed Central - PubMed

Affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada. plansdor@bccrc.ca

ABSTRACT
The telomeres of most eukaryotes are characterized by guanine-rich repeats synthesized by the reverse transcriptase telomerase. Complete loss of telomerase is tolerated for several generations in most species, but modestly reduced telomerase levels in human beings are implicated in bone marrow failure, pulmonary fibrosis and a spectrum of other diseases including cancer. Differences in telomerase deficiency phenotypes between species most likely reflect a tumour suppressor function of telomeres in long-lived mammals that does not exist as such in short-lived organisms. Another puzzle provided by current observations is that family members with the same genetic defect, haplo-insufficiency for one of the telomerase genes, can present with widely different diseases. Here, the crucial role of telomeres and telomerase in human (stem cell) biology is discussed from a Darwinian perspective. It is proposed that the variable phenotype and penetrance of heritable human telomerase deficiencies result from additional environmental, genetic and stochastic factors or combinations thereof.

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Related in: MedlinePlus

Telomere loss: an imperfect tumour suppressor mechanism. Loss of telomeric DNA after replication or damage to telomeric DNA limits the proliferation of abnormal (stem) cells. The flaws (red arrow) in the telomere-related tumour suppressor mechanism are illustrated here in a hypothetical scenario involving the short (p) arm of human chromosome 17. Chromosome 17p was chosen for illustration because it has a short track of telomere repeats in a majority of normal individuals (Martens et al, 1998; Britt-Compton et al, 2006) and because abnormalities involving the p53 gene (located on 17p13.1) are present in a majority of human cancers. Critically short telomeres are presumed to activate a DNA damage response similar to DNA double strand breaks. This DNA damage response (presumably mediated through ATM and p53) will result in growth arrest or apoptosis in all cells in most instances. However, selection on the basis of intact DNA damage responses will favour rare cells with (1) defective DNA damage responses or (2) cells in which the short telomeres are fused (eliminating the DNA damage signal). This can lead to loss of p53, genome instability and a ‘mutator phenotype' as illustrated. Eventually, cells with high telomerase levels are selected to stabilize typically highly rearranged tumour genomes. Alternatively, some tumour cells may bypass the ‘telomere checkpoint' altogether by upregulation of telomerase activity earlier in tumour development.
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f2: Telomere loss: an imperfect tumour suppressor mechanism. Loss of telomeric DNA after replication or damage to telomeric DNA limits the proliferation of abnormal (stem) cells. The flaws (red arrow) in the telomere-related tumour suppressor mechanism are illustrated here in a hypothetical scenario involving the short (p) arm of human chromosome 17. Chromosome 17p was chosen for illustration because it has a short track of telomere repeats in a majority of normal individuals (Martens et al, 1998; Britt-Compton et al, 2006) and because abnormalities involving the p53 gene (located on 17p13.1) are present in a majority of human cancers. Critically short telomeres are presumed to activate a DNA damage response similar to DNA double strand breaks. This DNA damage response (presumably mediated through ATM and p53) will result in growth arrest or apoptosis in all cells in most instances. However, selection on the basis of intact DNA damage responses will favour rare cells with (1) defective DNA damage responses or (2) cells in which the short telomeres are fused (eliminating the DNA damage signal). This can lead to loss of p53, genome instability and a ‘mutator phenotype' as illustrated. Eventually, cells with high telomerase levels are selected to stabilize typically highly rearranged tumour genomes. Alternatively, some tumour cells may bypass the ‘telomere checkpoint' altogether by upregulation of telomerase activity earlier in tumour development.

Mentions: If one accepts that telomere loss indeed evolved to limit the growth of pre-malignant cells in human beings, it should be noted that this mechanism has two serious flaws (Figure 2). First, the mechanism is subject to failure when two chromosome ends with insufficient telomere repeats fuse with each other. Such fusion events (e.g. between sister chromatids or between different chromosome ends) will extinguish the DNA damage signals that originated from the short telomeres. The removal of this checkpoint is predicted to allow cells to enter mitosis. Dicentric chromosomes formed by end-to-end fusion are likely to break on mitosis and initiate cycles of chromosome bridge/breakage/fusion (de Lange, 1995). This type of genome instability greatly facilitates deletion and amplification of genes and, as a result, the malignant evolution of (pre-) malignant cells. Second, by limiting the growth of (pre-) malignant cells, the DNA damage response triggered by short telomeres (d'Adda di Fagagna et al, 2003) will become subject to strong negative selective pressure. Such selection favours cells with defective DNA damage responses. Indeed, this seems a plausible mechanism, whereby most human tumours acquire defective DNA damage responses (e.g. over half of all human cancers have mutations in the p53 gene (Vousden and Lane, 2007)). As DNA damage responses are upstream in many different DNA repair pathways, cells selected on the basis of their inability to respond appropriately to short telomeres will display defects in several different DNA repair pathways. Indeed, it seems plausible that genome instability triggered by unstable chromosome ends in cells with defective DNA damage response result in the ‘mutator cell' phenotype that is characteristic of many tumour cells (Loeb, 2001). That chromosomal instability can be initiated by disruption of telomere function and that microsatellite instability and other genomic alterations often seen in cancer cells could arise from defective DNA damage responses indirectly selected by telomere shortening does not seem to be widely accepted (Michor et al, 2005). These ideas nevertheless seem plausible and worthy of further investigation. Apart from the difficulty of finding suitable model organisms, such studies are complicated by the transient period of rampant genome instability driven by telomere dysfunction. Sooner or later, most abnormal cells typically stabilize their chromosome ends (and at that stage typically highly abnormal genomes) by upregulation of telomerase activity (Kim et al, 1994). The frequent amplification of the telomerase reverse transcriptase gene in human lung cancer suggests that break–fusion–bridge cycles involving chromosome 5p is frequently involved in the upregulation of telomerase activity in those cells (Weir et al, 2007; Kang et al, 2008).


Telomeres and disease.

Lansdorp PM - EMBO J. (2009)

Telomere loss: an imperfect tumour suppressor mechanism. Loss of telomeric DNA after replication or damage to telomeric DNA limits the proliferation of abnormal (stem) cells. The flaws (red arrow) in the telomere-related tumour suppressor mechanism are illustrated here in a hypothetical scenario involving the short (p) arm of human chromosome 17. Chromosome 17p was chosen for illustration because it has a short track of telomere repeats in a majority of normal individuals (Martens et al, 1998; Britt-Compton et al, 2006) and because abnormalities involving the p53 gene (located on 17p13.1) are present in a majority of human cancers. Critically short telomeres are presumed to activate a DNA damage response similar to DNA double strand breaks. This DNA damage response (presumably mediated through ATM and p53) will result in growth arrest or apoptosis in all cells in most instances. However, selection on the basis of intact DNA damage responses will favour rare cells with (1) defective DNA damage responses or (2) cells in which the short telomeres are fused (eliminating the DNA damage signal). This can lead to loss of p53, genome instability and a ‘mutator phenotype' as illustrated. Eventually, cells with high telomerase levels are selected to stabilize typically highly rearranged tumour genomes. Alternatively, some tumour cells may bypass the ‘telomere checkpoint' altogether by upregulation of telomerase activity earlier in tumour development.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2722246&req=5

f2: Telomere loss: an imperfect tumour suppressor mechanism. Loss of telomeric DNA after replication or damage to telomeric DNA limits the proliferation of abnormal (stem) cells. The flaws (red arrow) in the telomere-related tumour suppressor mechanism are illustrated here in a hypothetical scenario involving the short (p) arm of human chromosome 17. Chromosome 17p was chosen for illustration because it has a short track of telomere repeats in a majority of normal individuals (Martens et al, 1998; Britt-Compton et al, 2006) and because abnormalities involving the p53 gene (located on 17p13.1) are present in a majority of human cancers. Critically short telomeres are presumed to activate a DNA damage response similar to DNA double strand breaks. This DNA damage response (presumably mediated through ATM and p53) will result in growth arrest or apoptosis in all cells in most instances. However, selection on the basis of intact DNA damage responses will favour rare cells with (1) defective DNA damage responses or (2) cells in which the short telomeres are fused (eliminating the DNA damage signal). This can lead to loss of p53, genome instability and a ‘mutator phenotype' as illustrated. Eventually, cells with high telomerase levels are selected to stabilize typically highly rearranged tumour genomes. Alternatively, some tumour cells may bypass the ‘telomere checkpoint' altogether by upregulation of telomerase activity earlier in tumour development.
Mentions: If one accepts that telomere loss indeed evolved to limit the growth of pre-malignant cells in human beings, it should be noted that this mechanism has two serious flaws (Figure 2). First, the mechanism is subject to failure when two chromosome ends with insufficient telomere repeats fuse with each other. Such fusion events (e.g. between sister chromatids or between different chromosome ends) will extinguish the DNA damage signals that originated from the short telomeres. The removal of this checkpoint is predicted to allow cells to enter mitosis. Dicentric chromosomes formed by end-to-end fusion are likely to break on mitosis and initiate cycles of chromosome bridge/breakage/fusion (de Lange, 1995). This type of genome instability greatly facilitates deletion and amplification of genes and, as a result, the malignant evolution of (pre-) malignant cells. Second, by limiting the growth of (pre-) malignant cells, the DNA damage response triggered by short telomeres (d'Adda di Fagagna et al, 2003) will become subject to strong negative selective pressure. Such selection favours cells with defective DNA damage responses. Indeed, this seems a plausible mechanism, whereby most human tumours acquire defective DNA damage responses (e.g. over half of all human cancers have mutations in the p53 gene (Vousden and Lane, 2007)). As DNA damage responses are upstream in many different DNA repair pathways, cells selected on the basis of their inability to respond appropriately to short telomeres will display defects in several different DNA repair pathways. Indeed, it seems plausible that genome instability triggered by unstable chromosome ends in cells with defective DNA damage response result in the ‘mutator cell' phenotype that is characteristic of many tumour cells (Loeb, 2001). That chromosomal instability can be initiated by disruption of telomere function and that microsatellite instability and other genomic alterations often seen in cancer cells could arise from defective DNA damage responses indirectly selected by telomere shortening does not seem to be widely accepted (Michor et al, 2005). These ideas nevertheless seem plausible and worthy of further investigation. Apart from the difficulty of finding suitable model organisms, such studies are complicated by the transient period of rampant genome instability driven by telomere dysfunction. Sooner or later, most abnormal cells typically stabilize their chromosome ends (and at that stage typically highly abnormal genomes) by upregulation of telomerase activity (Kim et al, 1994). The frequent amplification of the telomerase reverse transcriptase gene in human lung cancer suggests that break–fusion–bridge cycles involving chromosome 5p is frequently involved in the upregulation of telomerase activity in those cells (Weir et al, 2007; Kang et al, 2008).

Bottom Line: Complete loss of telomerase is tolerated for several generations in most species, but modestly reduced telomerase levels in human beings are implicated in bone marrow failure, pulmonary fibrosis and a spectrum of other diseases including cancer.Here, the crucial role of telomeres and telomerase in human (stem cell) biology is discussed from a Darwinian perspective.It is proposed that the variable phenotype and penetrance of heritable human telomerase deficiencies result from additional environmental, genetic and stochastic factors or combinations thereof.

View Article: PubMed Central - PubMed

Affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada. plansdor@bccrc.ca

ABSTRACT
The telomeres of most eukaryotes are characterized by guanine-rich repeats synthesized by the reverse transcriptase telomerase. Complete loss of telomerase is tolerated for several generations in most species, but modestly reduced telomerase levels in human beings are implicated in bone marrow failure, pulmonary fibrosis and a spectrum of other diseases including cancer. Differences in telomerase deficiency phenotypes between species most likely reflect a tumour suppressor function of telomeres in long-lived mammals that does not exist as such in short-lived organisms. Another puzzle provided by current observations is that family members with the same genetic defect, haplo-insufficiency for one of the telomerase genes, can present with widely different diseases. Here, the crucial role of telomeres and telomerase in human (stem cell) biology is discussed from a Darwinian perspective. It is proposed that the variable phenotype and penetrance of heritable human telomerase deficiencies result from additional environmental, genetic and stochastic factors or combinations thereof.

Show MeSH
Related in: MedlinePlus