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Telomere states and cell fatesElizabeth H. Blackburn

Departments of Biochemistry and Microbiology, University of California, San Francisco, San Francisco, California 94143-0448, USA............................................................................................................................................................................................................................................................................

Telomere length has frequently been used as a means to predict the future life of cells. But by itself it can be a poor indicator ofageing or cell viability. What, then, is the important property of a telomere? Here recent findings are integrated into a new,probabilistic view of the telomere to explain how and when it can signal not only its own fate but also that of a cell.

T elomeres are special functional complexes at the ends ofeukaryotic chromosomes. Linear DNA molecules, suchas eukaryotic chromosomal DNAs, require mechanismsbesides the conventional DNA polymerases to completethe replication of their ends. This is achieved by the

ribonucleoprotein enzyme telomerase, which balances terminalDNA losses by lengthening the ends of eukaryotic telomeric DNAthrough RNA-templated addition of tandemly repeated telomericsequences. Another hazard of having the chromosomal DNA inlinear form is that telomeres must be prevented from undergoingend-to-end fusion, which is the normal way of repairing chromo-some-internal DNA ends produced by DNA breakage. Telomerefusion results in chromosome instability and must therefore beavoided.

In proliferating cells lacking functional telomerase, the popula-tion of heterogeneously sized telomeres progressively shortens andthe cell population as a whole eventually undergoes senescence.Experimentally disrupting telomerase action causes telomere short-ening and cellular senescence1 (also reviewed in ref. 2). Conversely,in some experiments activating telomerase in certain humansomatic cells, which lack telomerase activity when grown in primaryculture, caused telomere lengthening and immortalized the cells3,4.Hence the view emerged that a ‘critical length’ was the property oftelomeres that caused cellular senescence.

Recent work in several systems has uncovered a more complexrelationship between telomere length and cell proliferative capacity.Here a new way to link telomeres to cellular senescence is proposed.The central concept is that the telomere is a dynamic nucleoproteincomplex that can switch stochastically between two states: cappedand uncapped. Capping is functionally defined as preserving thephysical integrity of the telomere, allowing cell division to proceed.However, regulated uncapping occurs normally in dividing cells,with the crucial property of a functional telomere being a highprobability that it will rapidly switch back to a capped state. Leftuncorrected too long, the uncapped state elicits cell-cycle arrest orother responses. Crucially, this probabilistic model identifies telo-mere capping status, as opposed to telomere length alone, as theimportant property relevant to telomere function. Factors, such astelomere length, that impinge on telomere function can now beevaluated in terms of their effects on telomere capping states.

Telomere length does not seal the fate of a cellTelomere shortness has often been assumed to indicate the numberof times a cell has divided and can be expected to divide. For cells inculture lacking telomerase, this mitotic ‘clock’ theory holds trueexperimentally5,6. It is also applicable to knockout mice lackingactive telomerase, which display progressive telomere shortening,both as the animals age and over increasing generations7,8. In somenormal somatic cells of adult humans and wild mice telomerelengths decrease with age9,10, leading to the suggestion that telomereshortening contributes to the organismal ageing by limiting cellproliferation. Recent studies show, however, that cultured fibro-blasts (which lack active telomerase) from older people reached

senescence in vitro no faster than fibroblasts taken from youngerpeople, suggesting that limited cell proliferation in vitro is notsimply related to age in humans11. Furthermore, when telomerase isactive a ‘mitotic clock’ model does not apply; by stabilizingtelomeres, telomerase effectively moves back the hands of anysuch ‘clock’. This is of direct interest for human studies becausetelomerase is active not only in human germline, embryonic andstem cells, but also in several types of normal adult proliferatingsomatic cells—in the immune system, skin, intestinal lining andhair follicles. Telomeres in human blood cell populations showcomplex length changes with age12, actually lengthening in certainimmune system cells of adult humans and toads13,14.

Telomere length is strongly influenced by many genetic, and otherfactors. Thus, in the same cell type telomeres can be longer in an oldperson than in another, younger person10,15. Hence only whengenetic and other conditions are strictly controlled are the factorsdetermining telomere functionality unmasked.

One such factor is the presence of active telomerase itself. In twobudding yeasts, Saccharomyces cerevisiae and Kluyveromyces lactis,cells lacking catalytically active telomerase ceased dividing after aperiod of telomeric shortening. However, cells of otherwise isogenicstrains expressing certain hypomorphic, but catalytically fullyactive, mutant telomerases continued to divide normally andindefinitely, despite their telomeres becoming and remainingmuch shorter than the shortest telomeres in the telomerase-lackingcontrol cells, which had stopped dividing. This was found with avariety of hypomorphic telomerases that retained enzyme activitybut caused telomeres to be short but stable16,17 (also reviewed in ref.18). Telomere shortness may therefore be clearly uncoupled fromloss of function, with the presence or absence of active telomerasebeing the critical factor.

Strikingly similar results have been obtained in human cells.Normal cultured endothelial cells and SV40 T-antigen-transformedfibroblasts lack telomerase activity, and telomeres shorten as theydivide. Without telomerase activation, the endothelial cells senesceand the transformed human fibroblasts undergo crisis, character-ized by chromosomal instabilities and failure to proliferate. Expres-sing telomerase from a constitutive retroviral promoter effectivelyimmortalized both cell types. As in the yeast experiments, althoughthe cells continued to proliferate, the telomeres shortened furtherand remained stably shorter than in the control cells at the pointwhen they had stopped proliferation19,20. Similar results were foundwith transformed fibroblasts that had spontaneously immortalizedand activated their endogenous telomerase21. Remarkably, thetransformed fibroblasts with experimentally activated telomerasealso had fewer chromosomal end-to-end fusions (indicative oftelomere failure) than did control cells, which entered crisis despitetheir longer telomeres. Hence, in yeasts and human cells, enzyma-tically competent telomerase has a protective effect on very shorttelomeres that, in its absence, would have caused cells to stopdividing. Notably, the presence of enzymatically competent telo-merase is not apparently required when telomeres are sufficientlylong; only when telomere length falls into a certain range does the

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presence or absence of telomerase become a critical factor19,22.

A two-state model of telomere cappingIf telomere length does not always indicate whether a telomere isfunctional, what does? As telomeres protect the ends of chromo-somes from fusion (end-to-end joining) and its deleterious con-sequences, telomere capping has been described as protecting thetelomere from being seen as a broken end. A DNA break within achromosome is sensed and responded to by the DNA damage-response machinery of the cell, with the result that, following cell-cycle arrest to allow time for the repair, the DNA break is fixed byend-to-end rejoining. Yet surprisingly, the DNA end-joiningresponse protein Ku is specifically located at telomeres23,24. More-over, Ku, as well as certain components of other DNA damage-response pathways, are actually needed for telomere mainte-nance25–28. Mutating the genes encoding DNA damage responsekinases (TEL1 and MEC1 in budding yeast, tel1+ and rad3+ infission yeast, and ATM in humans), a DNA damage checkpointprotein (MRT-2 in the nematode), or poly-(ADP ribose) poly-merase, which acts at DNA breaks, causes telomeres to becomeshort and prone to fusions28–30 (also reviewed in ref. 18).Importantly, genetic experiments show that TEL1 and MEC1(and probably MRT-2 in the nematode) are needed specificallyfor telomerase to act on telomeres27. Therefore, the telomereactually has to look like a DNA break for telomerase to act andthereby recap the telomere. This implies that a telomere con-tinually sustains some judiciously regulated degree of uncapping.These findings turn on its head the previous idea of how atelomere protects a chromosome end. They can be integratedwith the molecular information on telomeres into a dynamictwo-state model for telomeres, involving their switching betweenuncapped or capped states (Fig. 1).

First, this model provides a new framework to rationalize therecent results linking telomeres and DNA damage signalling in cells.The DNA damage response elicited on sensing an uncappedtelomere or other broken DNA end brings important enzymes tothese ends. Now telomere function can be envisaged as regulatingand channelling the active and sensitive surveillance DNA damageresponse, which can detect even a single DNA break in a cell, into anappropriate telomere-specific response that maintains the integrity

of the telomere. Thus, a crucial telomere-specific property of anuncapped telomere is to divert the DNA damage response intotelomerase action rather than into DNA end-to-end joining31. Asdescribed above, active telomerase helps even very short telomeresto be functionally capped. Possibly, once targeted to the telomere bythe DNA damage response, the active telomerase in turn signalsback to the cell, reassuring it to keep dividing. Another appropriateresponse to an uncapped telomere is homologous recombination,which in the absence of telomerase commonly acts on telomericDNA regions to extend them22. Only when all these processes fail docell-cycle exit or telomere end-joining ensue.

Second, the model ties molecular properties of a telomere, andtelomere length, to capping. Much evidence fits a model in whichthe high local concentration of proteins nucleated on the tandem-telomeric repeat array is conducive to formation of a highlycooperative complex (see Box 1). In this model, the complex canswitch between physical states corresponding to functionallycapped and uncapped. Longer telomeres (with more repeats andthus more protein-binding sites) are more likely to switch into thecapped state structure than are shorter telomeres32,33. The model canexplain why, in cells with telomerase, the lengths of the populationof telomeres are kept within well-defined limits. A shortenedtelomere elicits telomerase action, increasing its probability ofswitching to the capped state. On recapping, the resulting telomericDNA–protein complex acts as a gatekeeper to control telomeraseaction (as well as recombination and degradative activities asso-ciated with repair pathways). Shortening by incomplete replicationor degradation increases the probability of uncapping again. Inaddition to length, active telomerase and several other molecularcomponents of the telomeric DNA–protein complex collaboratesynergistically to affect this dynamic balance between capped anduncapped states33–36 (see Box 1).

Two states of cellsCellular senescence is commonly described as cells being able todivide a finite number of times, with senescence occurring onlywhen telomeres reach a critical short length. Usually implicit is theidea that the ‘young’ cells, which are all dividing at the beginning ofthe passaging, are free of ‘aged’ phenotypes until, following a period

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Box 1Capping function is provided by a mutually reinforcing set ofmolecular components

The tandem array of telomeric-DNA repeats at each chromosome endattracts and binds a set of sequence-specific DNA-binding proteins.These in turn bind a further set of proteins to assemble an inferredhigher order complex nucleated on the telomeric DNA repeats18,33,44.The telomeric complex exists in two states that determine telomerecapping. These may be analogous to the repressed (silenced) andnon-repressed states of heterochromatin, as some of the proteins inthe telomeric complex that affect capping in yeast are the same onesthat silence expression of genes placed near a telomere or at themating type loci (reviewed in ref. 33). Such silencing is characterized byepigenetic states that are stable for several cell divisions. Molecularevidence for similarly semi-stable telomere capping is seenexperimentally in telomeres that have had one or more componentsmutated: they show sudden changes in telomere length regulation,switching abruptly and stochastically to an unregulated state32,45.

Known molecular determinants of capping include activetelomerase19,45, structural proteins of the higher order telomericcomplex, and particularly, the properties of the DNA–proteincomplexes at the very tip of the telomeric tract31,35,36,45–47. All thesecomponents act synergistically in capping: compromising one can beharmless, but disrupting two or more often causes uncapping35,46.Thus, whether a telomere of a given length is uncapped depends onthe status of the other capping components of a telomere.

Shorteningor

lack of activetelomerase

Cappedtelomere

Celldivides

Fusedtelomeres

Signalto cellUncapped

telomere

ActiveDNA damage

response complex

Exitcell

cycle

TelomeraseHomologous

recombination DNAend joining

Chromosomeinstability

Figure 1 Telomere switching. The appropriate response to the uncapping of atelomere is action by telomerase (primarily) or homologous recombination, protectingand/or elongating the telomere so that cell cycling can resume. Non-homologous end-joining of telomeres can occur, fusing them and removing the immediate damagesignal, but when cell divisions resume the fused chromosomes are unstable. If none ofthese ways of capping occurs, the response of a normal cell is exit from the cell cycleor, in certain mammalian cells, cell suicide (apoptosis)47,48.

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of telomere shortening during the passaging, critically short telo-meres appear in the ‘old’ cells. Implicit is the idea of an inbuilt delaybefore senescence is reached. But a significant (although infre-quently cited) literature dealing with the behaviour of individualcells reveals a different picture (for example, refs 37, 38; reviewed inref. 39).

Quantitative examinations, on a cell-by-cell basis, of normalhuman and mouse somatic cells in culture have shown that thesecells exist in two states: cycling and exited from the cell cycle. Evenfrom the very beginning of passaging, cells are stochastically drop-ping out of the cycling population. They do so with ever-increasingfrequency until the population as a whole ceases doubling38.Notably, even late in the passaging any cells still in the cyclingstate are cycling as fast as those early in the passaging38,40. Hence, theonly difference between early and late passages is the frequency ofcycling versus non-cycling cells; those cycling cells that are ‘old’ byvirtue of their passage number are not significantly different fromthe cycling cells early in the passaging.

This well-documented stochastic two-state behaviour of individ-ual cells in a population matches remarkably well with the beha-viour predicted if the shortening telomeres in cells dividing withouttelomerase are in a two-state population as described above (Fig. 2).In this model, even at the beginning of the passaging, the telomeres,although relatively long, are predicted to have a finite (althoughinitially low) probability of becoming uncapped, as there is notelomerase present. The lack of telomerase precludes recapping, andthe uncapped telomere signals the cell to exit the cell cycle. As thecells undergo their divisions without telomerase, the telomerepopulation as a whole shortens, increasing the probability that atany point a telomere will stochastically switch to an uncapped state.The probability of any cell exiting the cell cycle correspondinglyincreases during culturing.

This new framing of the connection between telomere shorteningand cellular senescence differs from former descriptions by intro-ducing the concept of a stochastic and increasing probability of

switching to the uncapped/non-cycling state. It can explain severalobservations. In human cells in culture, two mitotic sister cells canhave vastly different proliferative potentials37 even though they havetelomeres that are similar in length (reviewed in ref. 39). Simplestochastic switching behaviour of telomeres accounts for both thegrowth kinetics of cultured cells, discussed above, and the largeamount of information about the molecular components of telo-mere capping. It can also account for the observation that intelomerase knockout mice, the telomere fusions and phenotypiceffects of telomerase deficiency increase steadily in frequency andseverity with increasing generations, rather than showing upabruptly only in late generations7,41,42. In yeasts, cellular senescenceis also stochastic and progressive in the cell population (see, forexample, ref. 22). Importantly, the new model obviates the need todefine a ‘critical’ telomere length. Instead, whether a telomere willbecome uncapped is expressed as a probabilistic function influencedby several factors, only one of which is its length.

ImplicationsUnderstanding how telomeres function and how telomerase exertsits protective effects will be necessary if telomerase is to be appliedeffectively for medical use. New results have necessitated therethinking of some previously held ideas about telomeres. Theaccumulated data show that telomere length alone cannot betaken as an indicator of the number of times the cells can or diddivide, nor of the age of an organism. Thus, we have to look beyondlength to understand telomere functionality. New questions havearisen: what is the precise molecular nature of the two telomericstates? How do the many identified parts of this cellular systems—telomerase, the DNA damage-response pathways and the differentcomponents of telomeres—act together to ensure telomeric andhence genomic stability? Such interactions can impact on theproliferation of both healthy and cancerous cells. Increasingly,investigations into a variety of biological processes point to theview that stochastic stabilization of one of two functionally differentphysical states can underlie many seemingly deterministic phenom-ena in biology43. The stochastic behaviours of telomeres and cellsmay provide another example of this. M

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= Cycling= Non-cycling (arrested)

= Capped= Uncapped

Cycling statusof cells

Lengths and cappingstates of telomeres

Passage

Early

Middle

Late

Overall populationgrowth rate

Fast

Intermediate

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(Senescence)

Figure 2 Stochastic uncapping of telomeres and cellular senescence kinetics. Aprobabilistic two-state switching behaviour of telomeres accounts for the two-statecell kinetics of primary cultures of normal mouse and human glial cells andfibroblasts38,40. Early in culturing most telomeres are functionally capped (yellow) andmost cells are cycling (yellow cells), but, lacking telomerase, a finite fraction of thetelomeres stochastically became uncapped (blue), causing cell-cycle exit (blue cells).This fraction increases steadily during culturing as the telomeres shorten, increasingtheir probability of stochastically uncapping, until net growth of the cell populationceases (senescence).

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AcknowledgementsI thank C. Gross, I. Herskowitz, B. Panning and C. Smith for discussions and comments onthe manuscript.

Correspondence should be addressed to E.H.B. (e-mail: telomer@itsa.ucsf.edu).

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