Telomeres and disease PM Lansdorp Loss of telomere repeats with replication No or low telomerase activity No advantage rare p53 mutation Normal p53 allele still present Most cells stop proliferation when too many short telomeres accumulate End-to-end fusions, formation of dicentric chromosomes: extinction of DNA damage signal originating from short telomeres Replication chromatids, progression cell cycle: mitosis Loss of heterozygosity Loss of normal p53 allele Selection pre-existing p53 mutant Loss of p53 function: ‘mutator phenotype’ Increased genetic and chromosomal instability: continued proliferation in the presence of short telomeres, more end-to-end fusions, no functional DNA repair Human chromosome 17 p53 p q Transformation, proliferation, damage to telomeric DNA DNA damage response originating from short telomeres: strong selection for 1. chromosome fusion events 2. DNA damage response defects Normal segregation, continued proliferation Normal anaphase or Anaphase bridge Break in spindle Break in chromatid Loss of dicentric chromosome Deletion of variable part of 17p Malignant progression, continued proliferation 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. HSC turnover early in life, which is reﬂected in a rapid decline in the rate of telomere attrition after 3–4 years in human beings (Rufer et al, 1999) and 1–2 years in baboons (Baerlocher et al, 2007). The turnover of murine HSCs also drops quite abruptly, but at 4–6 weeks after birth (Bowie et al, 2007; Kim et al, 2007). The majority of transplantable HSCs in adult mice are derived from a very small pool of quiescent cells that divide less than 10 times over a lifetime (Wilson et al, 2008). The picture that is emerging is that HSCs are dividing very infrequently in adults and only switch from dormancy to self-renewal following transplantation or other stress conditions. Very limited turnover of adult stem cells is also compatible with the minimal loss of telomere length observed in granulocytes from normal human individuals between 20 and 60 years of age (Lansdorp, 2008) and the sequential recruitment of quiescent progenitors that was observed to sustain cell production in human long-term bone marrow cultures (Lansdorp and Dragowska, 1993). On the basis of telomere length data from different mam- malian species, it has been proposed that HSCs divide less than 200 times over a lifetime and that this number is evolutionarily conserved (Shepherd et al, 2007). If this num- ber is correct, it suggests that very few cell divisions in the haematopoietic system are ‘wasted’. The total number of & 2009 European Molecular Biology Organization blood cells required for life-long blood cell production in man can be calculated to be in the order of 4 1016 cells (B1012 cells/day 365 days 100 years). In theory, only 55 divisions of a single cell could satisfy this need (255 ¼ 4 1016). With inclusion of additional cell divisions required to compensate for inevitable cell death and loss through differentiation, estimates of less than 200 cell divi- sions over a lifetime seem reasonable. The estimate of the number of divisions in HSCs is at odds with the thousands of divisions proposed, for example stem cells in the gut (Potten et al, 2002). The notion that stem cells in the intestine of mice divide much more than those in the bone marrow is also at odds with data from mice that lack telomerase (Blasco et al, 1997; Liu et al, 2000) and turnover estimates of tissues, including blood and intestine, derived from 14C dating (Spalding et al, 2005). Mice that lack telo- merase show a loss of around 5 kb per generation (Blasco et al, 1997). Assuming a loss of 100 bp of telomeric DNA per cell division, subsequent generations of telomerase-null mice are calculated to be separated by B50 divisions. This esti- mate is in close agreement with independent estimates of 34–133 cell divisions in the male and 25 in the female germline (Figure 3, adopted from Drost and Lee, 1995). If intestinal stem cells were indeed to divide thousands of The EMBO Journal VOL 28 | NO 17 | 2009 2535