Telomeres Secondary article

Elizabeth H Blackburn, University of California, San Francisco, California, USA Article Contents
. Introduction
Telomeres are specialized DNA–protein structures that occur at the ends of eukaryotic . The Replication Paradox
chromosomes. A special ribonucleoprotein enzyme called telomerase is required for the . Structure of Telomeres
synthesis and maintenance of telomeric DNA. . Synthesis of Telomeric DNA by Telomerase
. Functions of Telomeres

Introduction . Telomere Homeostasis

. Alternatives to Telomerase-generated Telomeric DNA

Telomeres are the specialized chromosomal DNA–protein . Evolution of Telomeres and Telomerase

structures that comprise the terminal regions of eukaryotic

chromosomes. As discovered through studies of maize and somes. One critical part of this protective function is to
fruitfly chromosomes in the 1930s, they are required to provide a means by which the linear chromosomal DNA
protect and stabilize the genetic material carried by can be replicated completely, without the loss of terminal
eukaryotic chromosomes. Telomeres are dynamic struc- DNA nucleotides from the 5’ end of each strand of this
tures, with their terminal DNA being constantly built up DNA. This is necessary to prevent progressive loss of
and degraded as dividing cells replicate their chromo- terminal DNA sequences in successive cycles of chromo-
somes. One strand of the telomeric DNA is synthesized by somal replication.
a specialized ribonucleoprotein reverse transcriptase called
telomerase. Telomerase is required for both telomeric
DNA synthesis and for long-term maintenance of telo-
meres. Of the essential cis-acting eukaryotic chromosomal Structure of Telomeres
DNA elements – DNA replication origins, centromeres
and telomeres – telomeres have emerged as the most The protein–nucleic acid complex comprising the telomere
conserved in structure, function and metabolism among has two types of known core components: the telomeric
eukaryotes as diverse as single-celled protozoans, fungi, DNA, usually consisting of tandemly repeated specific
warm- and cold-blooded animals and plants. nucleotide sequences, and proteins. Telomeric DNA-
Telomeres are quite different from the termini of linear binding proteins bind to the telomeric DNA through
viral, non-nuclear plasmid, mitochondrial or various recognition of its nucleotide sequence, and in turn bind
bacterial DNA genomes. These genomic units solve the other proteins, to assemble a dynamic, higher order DNA–
problem of completely replicating their DNA in a variety protein complex. All the known functions of telomeres
of ways, distinct from those used by eukaryotic chromo- appear to require correct assembly of this DNA–protein
somal telomeres. Hence, it is in general useful to define complex. Additionally, recent data implicate the telomer-
telomeres of eukaryotic chromosomes separately from the ase ribonucleoprotein as another possible structural part
terminal structures found at the ends of other linear DNA of the telomere for at least some part of the cell cycle.
genomes.
Telomeric DNA sequences
A eukaryotic species has a characteristic telomeric repeat
The Replication Paradox sequence common to the ends of all its chromosomes. With
relatively rare exceptions, described below, the form of the
In eukaryotes, every chromosome normally consists of one essential telomeric DNA of eukaryotes is highly conserved.
long linear DNA molecule carrying the genetic informa- It consists of an array of tandemly repeated short
tion, complexed with a multitude of chromosomal sequences (repeat units), generally with short clusters of
proteins. The terminal region of telomeric DNA cannot guanine (G) residues on the strand oriented 5’ to 3’ toward
be replicated completely by the conventional semiconser- the chromosomal terminus (the G-rich strand). Represen-
vative DNA replication enzyme machinery that replicates tative examples of telomeric repeated sequences are shown
the rest of the chromosomal DNA. Such incomplete in Table 1. Within a species, this repeat unit sequence can be
replication is a consequence of two properties of this identically repeated (for example, 5’ TTAGGG 3’ in
semiconservative DNA replication machinery: the ability humans or TTGGGG in the ciliated protozoan Tetra-
of DNA polymerases to work only in the 5’ to 3’ direction, hymena thermophila), or show limited, species-character-
and their requirement for a nucleic acid primer. Telomeres istic variation between repeat units (for example, G1–3T
protect the genetic material carried by eukaryotic chromo- repeats in the budding yeast Saccharomyces cerevisiae).

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 Telomeres

The same telomeric sequence can occur in widely appears to be the need to bind Rap1 (or its functional
divergent species: the telomeric repeat sequence TTAGGG equivalent in other species). These telomeric duplex DNA-
is found not only in humans and other vertebrates but also binding proteins form a protein array along the tandem
in trypanosomes, some slime moulds and filamentous array of telomeric repeats. This array, in turn, binds other
fungi. A terminal stretch of this simple-sequence DNA, proteins, which do not themselves bind DNA directly. In
ranging from less than a hundred to thousands of base budding yeasts they include the proteins Sir2p, Sir3p and
pairs (bp), depending on the species, appears to be Sir4p and possibly Rif1p and Rif2p. These interact with
sufficient for telomere function. In human cells, a roughly Rap1p and among themselves, promoting formation of a
5 kb to 20 kb tract of this precisely repeated sequence is higher order DNA–protein complex at each telomere.
found at every telomere. Hence, about 0.02–0.06% by Telomeres cluster under the nuclear envelope in many
weight of the total genome is telomeric DNA. However, species, suggesting that additional protein–protein inter-
considerable variation in mean telomere length is common actions bring telomeres together in the nucleus and allow
in eukaryotes including humans. During S phase of the cell them to interact with nuclear structures.
cycle, which is the time at which telomeric DNA is thought
to be replicated, the G-rich strand of telomeres protrudes
beyond the duplex telomeric DNA repeats, forming a 3’
terminal overhang. The sequence of telomeric DNA is
Synthesis of Telomeric DNA
dictated by its need to interact with multiple components, by Telomerase
including telomeric structural proteins and telomerase, in
order to carry out telomeric functions. Telomerase is a ribonucleoprotein enzyme that adds
telomeric DNA directly to the end of one strand of the
telomeric DNA, at each end of every chromosome.
Telomeric structural proteins Telomerase enzymatic activity is responsible for synthesis
of the G-rich strand of telomeric DNA to replenish the 5’
The known telomeric structural proteins fall into two ends of the chromosomal DNA to make up for the loss of
general groups: those that bind telomeric DNA directly, terminal sequences resulting from normal semiconserva-
and those that interact, directly or indirectly, with the tive DNA replication. On average, in each cell generation
telomeric DNA-binding proteins. Some telomeric DNA- telomerase activity adds a short stretch of telomeric repeats
binding proteins bind single-stranded telomeric DNA and (equivalent to what is lost through incomplete DNA
others bind duplex telomeric DNA. replication or nucleolytic action) onto the telomeric ends.
A class of telomere structural proteins, of which the best Hence a primary function of telomerase in vivo is to
biochemically characterized is the ab heterodimer of the counterbalance the progressive shortening of the chromo-
ciliated protozoan Oxytricha, binds the protruding G-rich some from its ends in dividing cells.
strand with strong DNA sequence specificity. The ribonu- Telomere structure is dynamic, with telomere length
cleoprotein enzyme telomerase also binds the protruding representing the net result of activities that lengthen and
single-stranded end of the G-rich telomeric DNA strand in shorten telomeric DNA, in relatively short increments, in
order to extend it. Genetic data and some biochemical each cell generation. This was first discovered in haploid
evidence in yeast implicate the proteins Est1p and Est4p/ yeast, in which the behaviour of individual telomeric
Cdc13p as single-stranded G-rich telomeric DNA-binding molecules could be inferred. Over several cell divisions, the
proteins. A DNA end-binding protein complex with replicative descendants of each individual telomeric
relatively low sequence specificity, the protein Ku, is molecule became progressively more heterogeneous in
required for long-term maintenance of telomeres in yeast length with each cell division. A current model for telomere
and may be located at telomeres. Ku is required for DNA replication is shown in Figure 1. One telomeric region of a
end-joining reactions in mammals, so its action at chromosome is shown.
telomeres, which specifically have to avoid end-to-end If telomerase sometimes lengthens the full-length
joining reactions, is currently unexplained. daughter (produced from copying strand B in Figure 1)
A class of telomeric duplex DNA-binding proteins with and sometimes the incompletely copied daughter (pro-
a common DNA-binding structural motif has been duced from copying strand A), after repeated cycles the
identified in budding and fission yeasts and mammals. observed progressive increase in telomere length hetero-
These proteins bind double-stranded telomeric DNA geneity will be generated. A feature of this replication
sequence specifically and include Rap1p (budding yeasts), mechanism is that no longer is it critical to replicate every
Taz1p (fission yeast), and TRF1 and TRF2 of mammals nucleotide at the end of a chromosome, because of the
(products of the mammalian TERF1 and TERF2 genes). ‘buffer zone’ of telomeric repeats, which are substrates for
The diverse telomeric repeat units of budding yeasts (see addition of more repeats by telomerase.
Table 1) share a conserved 12-bp consensus Rap1p-binding
site. Hence one constraint on telomeric DNA sequences

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 Telomeres

A telomeres. In such healing, telomerase adds telomeric

3’ repeats directly onto the broken DNA ends lacking
3’
3’
telomeres. These ends can be generated either accidentally
5’ 5’
by events such as ionizing radiation, enzymatic cleavage or
B mechanical rupture, or by the developmentally pro-
(a) (b) (c) grammed, site-specific fragmentation of chromosomes
that occurs in the life cycles of ciliated protozoa and
Figure 1 Model for the role of telomerase in the replication of linear
chromosomal DNA termini in eukaryotes. (a) During the chromosomal certain nematode worms.
DNA replication phase of the cell cycle (S phase), a DNA replication fork
initiated from a replication origin within the chromosome moves toward Enzymatic reactions of telomerase
the chromosomal DNA terminus. The helicase associated with the
replication complex unwinds (curved arrow) the parental strands (marked Telomerase synthesizes its species-specific telomeric repeat
A and B). (b) The transiently free single-stranded G-rich DNA 3’ terminus of sequence by elongating a DNA primer. The 3’ end of the
strand A is extended by telomerase (thick arrow). In vitro, telomerase primer normally base pairs with the telomerase RNA
requires a single-stranded 3’ end of DNA as a primer, because the 3’ end of
the primer to be elongated is normally base-paired to the RNA template
templating region, and is extended by copying along the
sequence. It is thought that telomerase acts during the S phase, perhaps RNA template. The polymerization activity of the
using the opportunity afforded by the displacement of the complementary telomerase ribonucleoprotein enzyme is restricted to
strand. Leading strand synthesis (lower rightward arrow) toward the copying a discrete template sequence consisting of only a
chromosomal terminus copies all the way to the end of parental strand B, small internal portion of the telomerase RNA. This was
producing one full-length daughter DNA. (c) It has been suggested that an
as yet unidentified DNA-processing activity produces the 3’ overhang at the
first demonstrated with the Tetrahymena telomerase, in
telomere by nucleolytic removal of the terminal portion of the C-rich which the sequence 5’CAACCCCAA3’ in the telomerase
telomeric DNA strand. The G-rich strand A, including its newly extended RNA component serves as a template for the addition of
terminus, is copied by discontinuous lagging strand synthesis (zig-zag is TTGGGG repeats, the telomeric repeats of Tetrahymena
RNA primer) by the primase–polymerase-mediated discontinuous (Greider and Blackburn, 1989). Figure 2 shows the
synthesis typical of semiconservative DNA replication mechanisms.
Removal of the most distal RNA primer leaves a 5’ terminal gap, i.e. the
mechanism of addition of telomeric DNA for Tetrahymena
protruding G-rich strand 3’ overhang. telomerase. Site-directed mutagenesis of this template
sequence results in the synthesis of telomeric DNA
The telomerase ribonucleoprotein complementary in sequence to the mutated template
sequence. Comparable findings were later made for the
Telomerases are specialized ribonucleoprotein reverse telomerases of other species. Thus telomerase is an unusual
transcriptase enzymes, with essential RNA and protein reverse transcriptase that carries its own internal RNA
components. The template for telomeric DNA synthesis is template for DNA synthesis.
contained within the RNA moiety of telomerase. Telomer- The DNA primers used most efficiently by telomerases
ase was first discovered in the ciliate Tetrahymena in the are the G-rich strand telomeric sequences from a variety of
1980s by Elizabeth Blackburn and Carol Greider. It was eukaryotes. Introducing a foreign telomere DNA into a
discovered by identification of an in vitro enzymatic yeast or a human cell, for example, results in the host cell’s
activity that added tandem repeats of the Tetrahymena telomeric DNA sequence being added to the end of the
species-specific telomeric DNA sequence, TTGGGG, onto foreign telomere. In vitro, although completely nontelo-
the 3’ end of any G-rich strand telomere oligonucleotide meric sequences lacking any G residues can be utilized to
primer, independently of an exogenously added nucleic prime elongation by telomerase, this occurs relatively
acid template (Blackburn and Greider, 1985). The inefficiently. The telomerase ribonucleoprotein also has an
existence of such an activity had been predicted from the intrinsic endonucleolytic DNA cleavage activity. This can
in vivo behaviour of telomeres, which includes rapid cleave a DNA oligonucleotide base paired for at least some
changes in length of the telomeric DNA repeat tracts, of its length to the 5’ region of the RNA template sequence.
and direct addition of yeast telomeric DNA sequences onto
Tetrahymena telomeric DNA introduced into yeast cells. Protein components of telomerase
Telomerase activities were subsequently found by similar
The essential protein component for telomerase catalytic
approaches in other phylogenetically diverse eukaryotes –
activity is a reverse transcriptase of a class called TERT
ciliates, human, frog, mouse, nematode worm and plant
(telomerase reverse transcriptase). Core telomerase poly-
cells, yeasts and parasitic protozoans.
merization activity appears to be supplied by the telomer-
Telomerase is essential for the normal telomeric DNA
ase reverse transcriptase protein (encoded by the TERT
synthesis and long-term maintenance of telomeres in most
gene) and the telomerase RNA (encoded by the TER gene).
eukaryotes. Without functional telomerase, telomeres
TERTs share certain conserved amino acid motifs with
shorten and cells eventually lose the capability to
other reverse transcriptase proteins, such as the three
proliferate. Telomerase is also responsible for chromo-
aspartic acid residues common to nucleic acid poly-
some ‘healing’ as well as replenishment of preexisting
merases, but they also have signature features in these

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 Telomeres

Pseudoknot
5’
3’ b I IV
A ACCCCA AC
Base pairing
T T GGGG
5’
(a) 5’
a 3’
51 49 47 45 43
A A C C C C A A C
Template domain
5’
3’
Figure 3 An example of the conserved core secondary structure of
A ACCCCA AC
First round synthesis telomerase RNA of ciliated protozoa. The sequence of the templating
T T GGGG t t g domain nucleotides in Tetrahymena telomerase RNA is indicated
5’ (AACCCCAAC) and nucleotide numbers from the 5’ end of the RNA are
indicated. The conserved double-stranded RNA structures are shown as
(b)
ladders marked I and IV, and the two helical components of the pseudoknot
are ladders indicated as a and b. Adapted from Blackburn (1998).

conserved common core structure (Figure 3). Such structur-

5’ al conservation suggests that telomerase RNA has other
3’
A ACCCC A AC functions, besides solely providing a short internal
Translocation
T T GGGG t t g template. Some of these functions are likely to include
5’ features required for transcription, stability and assembly
(c)
of telomerase into a ribonucleoprotein. S. cerevisiae
telomerase is active in an oligomeric (minimally dimeric)
Figure 2 Polymerization of telomeric DNA by telomerase from the form containing at least two functional RNAs in a single
ciliated protozoan Tetrahymena. (a) The 3’ nucleotides of the G-rich primer telomerase ribonucleoprotein complex. Mutating con-
(red) base pair with the template region of the telomerase RNA, whose ribo
served secondary structures of telomerase RNA interferes
A and ribo C nucleotide residues are shown. (b) The G-rich primer is
elongated, copying the telomerase RNA template, making first round DNA with its assembly into a functional RNP.
extension products (lower case letters). (c) After copying the last (5’ end) of Multiple experiments provide compelling evidence that
the telomerase RNA template, the product can translocate and reposition base-specific interactions involving the telomerase RNA
for a second round of synthesis. play critical roles in essential active site functions of
telomerase, i.e. for the enzymatic activity itself (Blackburn,
motifs, as well as additional unique TERT-specific motifs 1998). In the yeasts S. cerevisiae and Kluyveromyces lactis,
(Nakamura and Cech, 1998). Telomerase RNA forms a mutating a few specific telomerase RNA bases can have the
complex with TERT and other telomerase-associated same effects as complete deletion of the telomerase RNA
proteins, whose roles are not well understood. These gene, even though the telomerase RNA is stably assembled
include a p80 subunit in Tetrahymena thermophila, and a with telomerase proteins into a ribonucleoprotein com-
larger mammalian p80 homologue containing additional plex. These effects include no detectable polymerization
protein domains, including a nucleoside triphosphate activity in telomerase activity assays in vitro, and progres-
binding domain. A p95 and a p43 subunit also are sive telomere shortening, slow growth and eventual cellular
associated with the telomerase of the ciliates Tetrahymena senescence, all phenotypes characteristic of yeast cells
and Euplotes respectively. unable to replenish their telomeric DNA. Various point
mutations in the template of the Tetrahymena telomerase
RNA also cause marked impairment of telomerase active
The essential telomerase RNA component of telomerase
site functions, including enzyme processivity and fidelity,
The RNA moieties of telomerase from many species have which cause telomere shortening and a severe cell
been identified. Each contains a telomere-templating senescence phenotype in vivo. The properties of the
sequence for synthesis of species-specific telomeric DNA endonuclease cleavage activity of telomerase are altered
repeats. The primary sequences and sizes of telomerase in specific ways when telomerase contains various mutated
RNAs have diverged very rapidly in evolution compared forms of telomerase RNA. The highly aberrant or
with, for example, ribosomal RNAs. Telomerase RNA nonfunctional telomerase activities caused by telomerase
ranges in size from 147 nucleotide bases in a ciliate to over RNA mutations could result from a distortion of the active
1.3 kilobases in budding yeasts. However, the telomerase site, or failure of the mutated RNA residue to contribute a
RNAs of groups of related organisms share a conserved critical functional group to the active site.
secondary structure. For example, the primary sequences
of ciliate RNAs differ greatly overall, yet all share a

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 Telomeres

Functions of Telomeres gradual shortening. Telomere CPR may be a general

alternative telomere maintenance pathway in eukaryotes,
Telomeres are required to attract the telomerase replica- including immortalized mammalian cells lacking telomer-
tion machinery to the chromosomal terminus, as well as to ase activity.
regulate its action there. In addition, telomeres are
essential for stabilizing eukaryotic chromosomes in a
variety of ways. Telomeres shield the chromosomal termini Telomerase as a potential component of the
from recognition by the DNA damage response system of telomere capping complex
the cell. They ‘cap’ chromosome ends, preventing them
Yeast telomerases bind their DNA elongation products
from being degraded or fused together. Such fused
relatively stably in vitro, and telomerase may stably
chromosomes mis-segregate in mitosis or meiosis. A
associate with the telomeric terminus in vivo. In the
broken nontelomeric chromosomal DNA end also signals
presence of functional telomerase, yeast and human cells
cell cycle arrest and suffers terminal degradation. Telo-
continue dividing and stably maintain telomeres at lengths
meres are often located under the nuclear envelope, and
well below the shortest telomeres detectable in cell cycle-
their specific association with the spindle pole body in
arrested cells that lack telomerase function. Recombina-
fission yeast is required for normal meiotic recombination.
tion in cells lacking functional telomerase takes place even
on long telomeres, while similarly long telomeres are not
Protection from DNA damage-induced cell subject to recombination events in cells with functional
telomerase. Hence functional telomerase bound to the
cycle arrest
chromosomal termini may contribute to the capping
Telomeres prevent chromosome ends from being mistaken function of telomeres.
for damaged or broken DNA. A broken DNA end, or the
removal of a telomere from a chromosome in a cell, signals
Roles of telomeres in mitosis
cell cycle arrest. Upon resumption of cell growth, the
chromosome missing a telomere is lost at an extremely high Experimentally altering the sequence at the very terminus
rate. A telomere that becomes too short also triggers a of the chromosome (by changing the telomerase RNA
similar cell cycle arrest and a DNA damage response. Thus, template sequence) in some cases prevents completion of
deleting or mutating the telomerase RNA or a telomerase nuclear anaphase because the mutant chromatids fail to
protein component causes progressive loss of telomeric separate their telomeres, often becoming stretched as the
repeats and, when even a single telomeric DNA tract in a cell cycle progresses and anaphase continues. In contrast,
cell falls below a critical length, cell cycle arrest leading to harbouring the same mutant sequences in the internal
declining cell growth capability (growth senescence). portions of the telomeric repeat tracts causes no adverse
Arrest ensues before the complete loss of telomeric repeats. effects, so long as wild-type repeat sequences are at the very
Failure of mammalian cells lacking telomerase to continue termini. These results suggest that telomere-mediated
proliferation could be related to such attrition of telo- chromosome stabilization involves correct binding of
meres. sequence-specific telomere-binding protein(s) to the sin-
gle-stranded DNA overhang and/or the distal duplex
telomeric DNA. In human cells in culture, preventing
Protection from recombination TRF2 from binding the telomeres also causes anaphase
Ends of linear eukaryotic chromosomal DNA that are chromosomal bridges, thought to result from telomere–
broken or have incomplete telomeric structures are subject telomere DNA fusions. In the yeast K. lactis, specific
to fusion, by nonhomologous recombination, to other mutated terminal telomeric repeats that cannot bind
broken DNA ends (but not to functional telomeric Rap1p normally, cause loss of telomere length regulation
termini). The resulting dicentric and other aberrent and failure to segregate chromosomes, although the
chromosomes are deleterious because they cannot segre- affected step in nuclear division is not identified.
gate properly. On the other hand, in cells lacking
telomerase function, homologous recombination between Roles of telomeres in meiosis
telomeric repeat tracts on different telomeres regenerates
lengthened telomeres and can indefinitely maintain telo- Early in meiotic prophase, the telomeres cluster under the
meres within a cell population. Such ‘telomere cap- nuclear envelope near the centrosome in many animals, or
prevented recombination’ or ‘telomere CPR’ is induced near the spindle pole body (the yeast version of the
by loss of telomere capping function. Such recombina- centrosome) in the fission yeast Schizosaccharomyces
tional repair occurs via unequal homologous crossovers pombe. This association facilitates meiotic recombination
between uncapped telomeric repeat tracts which are often between chromosome homologues and requires Taz1p in
much longer than wild type, but which are still subject to S. pombe. In S. cerevisiae, a telomerically located, meiosis-

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 Telomeres

specific protein, Tam1p/Ndj1p, is needed for normal synthesized by reverse transcription of (often) defective
crossover interference in meiotic recombination. How retroelements (Blackburn, 1998). In this way, the elonga-
Tam1p associates with telomeres is unknown. tion of chromosome ends in D. melanogaster is analogous
to the action of telomerase; both involve reverse transcrip-
tion to add DNA and hence balance the loss of terminal
DNA sequences through incomplete replication. Thus the
Telomere Homeostasis essential difference between D. melanogaster and more
typical eukaryotes may only be that in D. melanogaster the
The number of tandem repeats of the telomeric sequence at added DNA is synthesized by copying a substantial part of
the end of each chromosome is normally closely regulated, the retroelement RNA, so that DNA segments are
preventing telomeres from becoming too short or too long. infrequently added to broken or other chromosome ends
Normal telomere length homeostasis is maintained in large (several kilobase) increments, whereas the typical
through a dynamic balance between addition (by telomer- telomerase copies only a very short region of RNA, so that
ase) and loss of the terminal telomeric DNA, and requires lengthening of the chromosome occurs in small increments
telomerase action as well as a telomeric protein–DNA in most or all cell divisions. Perhaps D. melanogaster
complex. Without telomerase, each cell generation each represents a late-derived situation in evolution, in which a
chromosome end progressively loses an average of 5 bp sufficiently efficient HeT-A mechanism allowed the re-
of terminal DNA in yeasts, and 50–100 bp in mammalian quirement for telomerase to be bypassed.
cells. Addition of telomeric DNA to the chromosomal
ends by telomerase counterbalances this terminal DNA
attrition. Telomeric DNA in dipteran insects and plants
The lengths of all the telomeres in a cell fall within a set In the gnat Chironomus, the mosquito and the Allium genus
range in a given tissue and stage of life, which is of plants, yet another type of telomeric sequence appears to
characteristic of a given species. Telomere lengths vary have replaced telomerase-generated short telomeric re-
through changing the relative rates of DNA addition and peats. These species have longer (hundreds of base pair)
loss, contrasting with the relatively static behaviour of tandem repeats at the chromosomal end regions. These
internal regions of chromosomes. Telomere length is have the hallmarks of being generated through repeated
controlled by telomerase levels as well as multiple genetic unequal crossovers, and possibly represent a version of
factors and the metabolic state of the cell. The telomere- telomere CPR that has become the normal mode of
specific DNA-binding proteins Rap1p in budding yeasts, telomere maintenance in these species.
Taz1p in fission yeast and TRF1 (the TERF gene product)
in mammalian cells, negatively adjust telomere length by
regulating the action of telomerase, possibly by controlling
its access to the telomere. A critical component of Rap1p- Evolution of Telomeres and Telomerase
mediated telomere length regulation requires Rap1p
binding to the duplex telomeric repeats at the extreme Linear chromosomal DNA whose replication involves
telomeric terminus. In addition, optimal negative regula- telomerase-mediated addition of simple telomeric repeats
tion of telomere length by Rap1p involves nucleation of a is common to eukaryotes. Linear DNA, and the conse-
higher order protein complex, probably including the quent need for telomeric DNA function, may have been an
proteins Rif1p and Rif2p, by Rap1p. adaptation of the eukaryotic lineage to requirements
imposed by large genomic DNAs for faithful transmission
to progeny cells. The conservation of telomerase through-
out the eukaryotes in the form of a ribonucleoprotein and
Alternatives to Telomerase-generated phylogenetic comparisons of TERT sequences between
Telomeric DNA protozoans, yeasts and mammals suggest that telomerase
predated (or existed early after) the separation of
Retrotransposons in Drosophila melanogaster eukaryotes from prokaryotes. Telomerase RNA is func-
tionally involved in the enzymatic actions of telomerase to
Some insect species, including the silkmoth, have conven- a degree not seen in the various reverse transcriptases
tional telomeric repeats (see Table 1). However, no found in systems ranging from retroviruses to prokaryotes.
conventional short-repeat type of telomeric sequence has The presence of an RNA in telomerase whose function
been identified in the fruitfly Drosophila melanogaster. includes acting as a template for DNA synthesis is
Instead, retroelement-derived sequences called HeT-A intriguing in the context of the evolutionary transition
sequences, and possibly another class of retroelements, that is thought to have occurred from RNA to DNA
TART sequences, serve a telomeric role in this species. The genomes. In one model for the evolution of telomerase,
HeT-A elements added to the ends of chromosomes are telomerase is a molecular fossil, whose RNA moiety is a

6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

 Telomeres

relic of a catalytic RNA replicase ribozyme that copied Blackburn EH and Greider CW (1985) Identification of a specific
itself, an RNA genome, into an RNA copy. In this model, telomere terminal transferase activity in Tetrahymena extracts. Cell 43:
the RNA ancestor to telomerase acquired protein and the 405–413.
Greider CW and Blackburn EH (1989) A telomeric sequence in the RNA
ability to synthesize DNA. As protein components took
of Tetrahymena telomerase required for telomere repeat synthesis.
over a catalytic role, some lineages gave rise to the protein Nature 337: 331–337.
reverse transcriptases of modern eukaryotes and prokar- Nakamura TM and Cech TR (1998) Reversing time: origin of
yotes. However, in the case of telomerase, the RNA was telomerase. Cell 92: 587–590.
retained, and contributed functional groups to building the
active site necessary for activity of the TERT protein
Further Reading
catalytic aspartate residues. At least a portion of the RNA
also retained its template function. While the function of Blackburn EH (1990) Broken chromosomes and telomeres. In: Federoff
genome replication has been taken over by DNA- N and Botstein D (eds) The Dynamic Genome: Barbara McClintock’s
dependent DNA polymerases, telomerase, a specialized Ideas in the Century of Genetics. Cold Spring Harbor, New York: Cold
reverse transcriptase, is still used to maintain the ends of Spring Harbor Laboratory Press.
Blackburn EH and Greider CW (eds) (1995) Telomeres. Cold Spring
eukaryotic chromosomes. Harbor, New York: Cold Spring Harbor Laboratory Press.
Blackburn EH and Greider CW (1996) Telomeres, telomerase and
cancer. Scientific American 274: 80–85.
Chadwick DJ and Cardew G (eds) (1997) Telomeres and Telomerase.
References Ciba Foundation Symposium 211. Chichester: John Wiley and Sons.
Hiraoka Y, Henderson E and Blackburn EH (1998) Not so peculiar:
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2nd edn. Cold Spring Harbor, New York: Cold Spring Harbor Zakian VA (1996) Telomeres: Beginning to understand the end. Science
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