Does a Sentinel or a Subset of Short Telomeres Determine Replicative Senescence?

Abstract

The proliferative life span of human cells is limited by telomere shortening, but the specific telomeres responsible for determining the onset of senescence have not been adequately determined. We here identify the shortest telomeres by the frequency of signal-free ends after in situ hybridization with telomeric probes and demonstrate that probes adjacent to the shortest ends colocalize with gammaH2AX-positive DNA damage foci in senescent cells. Normal BJ cells growth arrest at senescence before developing significant karyotypic abnormalities. We also identify all of the telomeres involved in end-associations in BJ fibroblasts whose cell-cycle arrest at the time of replicative senescence has been blocked and demonstrate that the 10% of the telomeres with the shortest ends are involved in >90% of all end-associations. The failure to find telomeric end-associations in near-senescent normal BJ metaphases, the presence of signal-free ends in 90% of near-senescent metaphases, and the colocalization of short telomeres with DNA damage foci in senescent interphase cells suggests that end-associations rather than damage signals from short telomeres per se may be the proximate cause of growth arrest. These results demonstrate that a specific group of chromosomes with the shortest telomeres rather than either all or only one or two sentinel telomeres is responsible for the induction of replicative senescence.

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

“…Studies on human fibroblasts have shown that telomere shortening induces two checkpoints. The first checkpoint is activated in response to low levels of telomere dysfunction [3-5 dysfunctional telomeres per cell, (Zou et al, 2004)]. At this stage human fibroblasts enter a permanent cell cycle arrest, which is called replicative senescence (Wright and Shay, 1992).…”

Cancer and aging: the importance of telomeres in genome maintenance

“…Moreover, only a few dysfunctional telomeres per cell may be sufficient to elicit a cellular response [41,42].…”

“…These telomeric DNA damage foci contain phosphorylated histone H2AX (γ-H2AX) and a variety of other DNA damage response proteins such as the DNA damage inducible kinases (ATM, ATR, DNA-PK, CHK1 and CHK2), the RMN complex and the BRCT motif proteins MDC1/NFBD1 and 53BP1 [42,105,107,108] (Fig. 4).…”

Telomere length and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study

“…12,13 Therefore, using the same films as for mean telomere restriction fragment analysis, we also calculated the percentage of short telomeres (shorter than 5 kb) in each telomeric sample. This cutoff value was chosen as it identified the shortest 15% of telomeric DNA.…”

“…Proportion of short telomeres may more closely reflect cellular senescence of a subset of circulating leukocytes and vascular aging than mean telomere length, as has been suggested previously. 12,13 Indeed, in a study concerning 274 Danish twin pairs, the proportion of shortest telomeres was a better predictor of mortality than mean telomere length. 16 Accordingly, we recently reported that the proportion of shortest telomeres was a better predictor than mean telomere length of progression of renal disease in patients with type 1 diabetes.…”