Telomeres and disease

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.

Figure 1

What came first, the chicken or the egg? Chickens (and hens) can be regarded as the mortal carriers of immortal germline DNA. Natural selection results in somatic (stem) cells that do not devote more energy on DNA repair and tissue maintenance than is required for the reproductive strategy and corresponding lifespan of a particular species. According to the ‘disposable soma' theory, ageing is not actively programmed, but results from the accumulation of damage after reproduction (Kirkwood and Holliday, 1979). Long-lived species that reproduce after many years need more efficient DNA repair and better protection against tumour development than comparable species that reproduce within weeks or months. Somatic cells from long-lived species show loss of telomeric DNA with each division. Telomere loss is not readily observed in cells from most short-lived species. Most likely loss of telomeric DNA represents a tumour suppressor mechanism that does not exist as such in somatic cells from short-lived species.

Figure 2

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.

Figure 3

Estimated number of cell divisions in the female and male murine germline from one generation to the next (adapted from Drost and Lee, 1995). The number of cell divisions is given below the indicated developmental stages. Thus, to go from a fertilized egg to a blastocyst takes an estimated 6 divisions; 8 more divisions are needed to produce 150 primary gonadal cells; the latter go through 11 more divisions before cells commit to either the female germline (1 more cell division before mature oocytes is produced) or the male germline (in which the estimated number of divisions from stem cell to spermatocyte is 9). Production of spermatocytes in males continues throughout adult life. Estimates of the number of divisions at the level of spermatogonial stem cells are hampered by uncertainties that are similar to those discussed for haematopoietic and intestinal stem cells. For the (young) mice without telomerase in laboratory settings, it is estimated that at most 50 divisions separate one generation from the next.