TELOMERES AND HUMAN DISEASE: AGEING, CANCER AND BEYOND
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REVIEWS
TELOMERES AND HUMAN DISEASE:
AGEING, CANCER AND BEYOND
Maria A. Blasco
Abstract | Telomere length and telomerase activity are important factors in the pathobiology of
human disease. Age-related diseases and premature ageing syndromes are characterized by
short telomeres, which can compromise cell viability, whereas tumour cells can prevent
telomere loss by aberrantly upregulating telomerase. Altered functioning of both telomerase
and telomere-interacting proteins is present in some human premature ageing syndromes and
in cancer, and recent findings indicate that alterations that affect telomeres at the level of
chromatin structure might also have a role in human disease. These findings have inspired a
number of potential therapeutic strategies that are based on telomerase and telomeres.
The ends of chromosomes are formed by telomeres can be disrupted in disease. Indeed, activities that are
— special chromatin structures that are essential to pro- involved in chromatin assembly, telomerase activity and
tect these regions from recombination and degradation telomere-binding proteins are altered in some ageing-
activities1. In vertebrates, telomeres are composed of tan- related diseases and in cancer (FIG. 1; TABLE 1. I also dis-
dem repeats of the TTAGGG sequence that are bound cuss the generation of mouse models that are deficient
by specific proteins1. They are also the substrate for telo- for telomerase activity. These models have been crucial
merase, a DNA polymerase that can elongate them in in demonstrating that short telomeres in the mouse can
those cell types in which it is expressed2,3. Interestingly, lead to similar disease states to those associated with
telomeres continuously lose TTAGGG repeats in a way both normal ageing and premature ageing syndromes
that is coupled to cell division, owing to the incomplete in humans. These mouse models have also contributed
replication of linear chromosomes by conventional DNA to our understanding of how telomerase regulates the
polymerases — the so-called ‘end-replication problem’. balance between ageing and cancer. This knowledge
This progressive telomere shortening is proposed to has opened up the possibility of targeting telomerase
represent a ‘molecular clock’ that underlies organismal and telomere-binding proteins in therapeutic strategies
ageing2,3. In particular, telomere shortening to a criti- against cancer and ageing-related pathologies.
cal length results in loss of telomere protection, which
leads to chromosomal instability and loss of cell viabil- Telomeric chromatin and its regulation
ity. As an exception, germ cells and some cancer cells Telomere repeats, telomerase and T loops. Telomeres
express high levels of telomerase, which prevents critical are gene-poor, repetitive chromosomal regions that are
telomere shortening and maintains cell viability3. located adjacent to the more gene-rich subtelomeric
Defects in telomere length have been implicated regions (FIG. 1A). They span around 10–15 kb in humans
in the pathology of several age-related diseases and and 25–40 kb in mice1,2. The proteins that associ-
Telomeres and Telomerase premature ageing syndromes, as well as in cancer. In ate with these structures include the telomere repeat
Group, Molecular Oncology this review, I discuss recent advances in understanding binding factors 1 and 2, TRF1 and TRF2 (also known
Program, Spanish National the regulation of telomeres by chromatin-modifying as TERF1 and TERF2), which can directly bind to the
Cancer Centre (CNIO),
28029 Madrid, Spain. activities, telomere-binding proteins and telomerase. TTAGGG repeats and can also interact with other fac-
e-mail: mblasco@cnio.es These different levels of telomere regulation have tors, forming large protein complexes (see below for
doi:10.1038/nrg1656 provided new insights into how telomere function details).
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A Ca TRF1 complex
Telomeres
TANK
(altered in
some tumours)
POT1
G-strand overhang TRF1 (altered in
(altered in some tumours)
Subtelomeric
regions 150–200 nt some tumours)
PTOP
TRF2 RAP1
(altered in
3′ OH TIN2
some tumours)
TRF1 TRF2 (altered in
some tumours)
TTAGGG TTAGGG
Cb TRF2 complex
AATCCC AATCCC ERCC1 TRF2 (altered in
10–15 kb human (Xeroderma pigmentosum) some tumours)
25–40 kb mouse Telomerase
PARP2
MRE11/NBS1/RAD50
(Nijmegen breakage WRN
syndrome, Ataxia (Werner syndrome)
B telangiectasia-like
disorder) BLM
(Bloom syndrome)
ATM (Ataxia telangiectasia) KU86
T loop Cc Telomerase
TERC
TERT (Dyskeratosis
(aplastic anaemia, congenita, aplastic
altered in tumours) anaemia, altered
Strand invasion of
the G-strand overhang 5′ in tumours)
D loop
Restricted
3′ OH access of
telomerase DKC1
to telomeres (Dyskeratosis
congenita)
Figure 1 | Telomere structure and telomerase activity. A | The structure of mammalian telomeres. Telomeres contain a
double-stranded DNA region of TTAGGG repeats (green arrows) which is typically 10–15-kb long in humans and 25–40-kb long
in mice. Telomeres are characterized by a 150–200-nt long single-stranded overhang of the G-rich strand (G-strand overhang;
blue arrows). Note that the length of telomere repeats is not drawn to scale. Telomerase recognizes the 3′ OH at the end of the
G-strand overhang, leading to telomere elongation. Two main protein complexes are bound to telomeres, the telomere repeat
binding factor 1 and 2 complexes, TRF1 and TRF2. B | A telomere in a T-loop conformation. Strand invasion of the G-strand
overhang is highlighted in red. This conformation might prevent the access of telomerase to the 3′ OH at the chromosome end.
The components of the telomere repeat binding factor 1 (TRF1) (Ca) and 2 (TRF2) (Cb) complexes and the telomerase enzyme
(Cc) are shown. The human diseases in which expression of these components has been shown to be altered are indicated.
Note that the way that the complexes are shown is not necessarily an exact structural representation. ATM, ataxia telangiectasia
mutated; BLM, Bloom syndrome; DKC1, dyskeratosis congenita 1, dyskerin; ERCC1, excision repair cross-complementing 1;
KU86, Ku86 autoantigen related protein 1 (also known as XRCC5); MRE11, meiotic recombination 11; NBS1, Nijmegen
breakage syndrome 1; POT1, protection of telomeres 1; PTOP, POT1 and TIN2 organizing protein; RAD50, a DNA repair
protein; RAP1, repressor/activator protein 1; TANK, tankyrases; TERC, telomerase RNA component; TERT, telomerase reverse
transcriptase; TIN2, TRF1-interacting nuclear factor 2. Part B is modified, with permission, from EMBO Journal REF. 66 © (2005)
Macmillan Magazines Ltd.
Telomeres are also characterized by the fact that they to telomeres4–6 (FIG. 1B). Loss of telomere protection
end in a 150–200 nucleotide single-stranded overhang can occur due to loss of either TTAGGG repeats or
of the G-rich strand1 (FIG. 1A). Telomerase is a reverse telomere-binding factors, which leads to chromosomal
transcriptase, which is encoded by the Tert (telomerase end-to-end fusions and subsequent loss of cell viability.
reverse transcriptase) gene, that specifically recognizes Telomerase activity prevents the TTAGGG repeats from
the 3′-OH group at the end of this overhang. It elongates being shortened to below a critical length in those cells
telomeres by extending from this group using an RNA in which it is expressed, therefore protecting telomeres
molecule, which is encoded by the Terc (telomerase and maintaining cell viability.
RNA component) gene, as a template2,3 (FIG. 1A,C). The
G-strand overhang can also fold back and anneal with The chromatin structure of telomeres. Several studies
NUCLEOSOME the double-stranded region of the TTAGGG repeats have highlighted the fact that mammalian telomeres,
The structure responsible in to form a large telomeric loop known as the T loop4–6 besides being substrates for telomerase and the telomere
part for the compactness of a
(FIG. 1B). This has been proposed to represent a primor- repeat binding factors, are also bound by NUCLEOSOME
chromosome. Each nucleosome
consists of a sequence of DNA dial mechanism for chromosome end-protection, and arrays7. These arrays contain histones that have under-
wrapped around a histone core. could also function to restrict the access of telomerase gone specific modifications that are characteristic of
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Table 1 | Components of mammalian telomeres and their roles in human disease
Components Main roles Mouse model Main phenotypes Human disease
Chromatin regulators
HP1α, HP1β, HP1γ Telomere regulation None Not determined Unknown
SUV39H1/H2 Telomere regulation Viable Heterochromatin loss, centromeric Altered in cancer
defects, long telomeres, ↑ lymphoma
RB1/RBL1/RBL2 Telomere regulation Cells only (lacking all Heterochromatin loss, centromeric Altered in cancer
three proteins) defects, long telomeres, immortality
Trimethylated H3-K9 Telomere regulation ↓ H3-K9 in SUV39H1/ Heterochromatin loss, centromeric Altered in cancer
H2 knockouts defects, long telomeres
Trimethylated H4-K20 Telomere regulation None Heterochromatin loss, centromeric Altered in cancer
defects, long telomeres
Telomere-binding proteins
TRF1 Telomere regulation Embryonic lethal Normal telomere length/capping Overexpressed in
some tumours
TRF2 Telomere regulation, None Not determined Overexpressed in
DNA repair some tumours
POT1 Telomere regulation None Not determined Overexpressed in
some tumours
TIN2 Telomere regulation, Embryonic lethal Normal telomere length/capping Overexpressed in
heterochromatin some tumours
TANK1 Telomere regulation, None Not determined Overexpressed in
chromatid cohesion some tumours
TANK2, PTOP, RAP1 Telomere regulation None Not determined Unknown
DNA repair proteins
KU70/86, DNA-PKcs Telomere regulation Viable Premature ageing, aberrant telomere Altered expression in
length, loss of telomere capping cancer
MRE11/NBS1/RAD50 Telomere regulation Embryonic lethal Telomere phenotype unknown ATLD (Mre11 mutation),
NBS (Nbs1 mutation)
PARP2 Telomere regulation Viable ↑ Telomeric fusions Unknown
WRN, BLM Telomere regulation Viable Premature ageing and short telomeres Werner syndrome/
in a Terc KO background Bloom syndrome
ATM Telomere regulation, Viable ↑ Lymphoma, radiosensitive, ageing in Ataxia telangiectasia
DNA damage response a Terc KO background
ERCC1/XPF Telomere regulation, NER Postnatal death Severe sensitivity to DNA damage, Xeroderma
normal telomere length pigmentosum
RAD54 Telomere regulation Viable ↓ Homologous recombination, shorter Altered in cancer
telomeres, loss of capping
RAD51D Telomere regulation Embryonic lethal ↑ Chromosomal instability, shorter Altered in cancer
telomeres, loss of capping
XRCC3 Telomere regulation None Not determined Altered in cancer
MMR genes Recombination at telomeres Viable Infertile, ↑ cancer Altered in cancer
FANC genes Telomere regulation? Viable Infertile, radiosensitive Fanconi anaemia
Telomerase components
TERC Telomere-length Viable for limited Premature ageing, ↓ cancer, short Dyskeratosis congenita,
maintenance generations telomeres, loss of capping aplastic anaemia
TERT Telomere-length Viable for limited Short telomeres, loss of capping Aplastic anaemia
maintenance generations
DKC1 Telomere-length Embryonic lethal Dyskeratosis congenita Dyskeratosis congenita
maintenance
ATLD, ataxia telangiectasia-like disorder; ATM, ataxia telangiectasia mutated; BLM, Bloom syndrome; DKC1, dyskeratosis congenita 1, dyskerin; DNA-PKcs, DNA-
dependent protein kinase catalytic subunit; ERCC1, excision repair cross-complementing 1; FANC, Fanconi anaemia complementation group; H3-K9, histone 3 at lysine 9;
H4-K20, histone 4 at lysine 20; HP1α/β/γ, heterochromatin protein 1, α-, β- and γ-isoform; KO, knockout; KU70/86, Ku antigen protein 70 and 86; MMR, mismatch
repair; MRE11, meiotic recombination 11; NBS, Nijmegen breakage syndrome; NER, nucleotide excision repair; PARP2, poly(ADP-ribose) polymerase family 2; POT1,
protection of telomeres 1; PTOP, POT1 and TIN2 organizing protein; RAD50/51D/54, DNA repair protein 50, 51D and 54; RAP1, repressor/activator protein 1; RB1,
retinoblastoma 1; RBL1/2, retinoblastoma-like 1 and 2; SUV39H1/2, suppressor of variegation 3-9 homologue 1 and 2; TANK1/2, tankyrase 1 and 2; TERC, telomerase
RNA component; TERT, telomerase reverse transcriptase; TIN2, TRF1-interacting nuclear factor 2; TRF1/2, telomere repeat binding factor 1 and 2; WRN, Werner
syndrome; XRCC3, X-ray repair complementing defective repair in Chinese hamster cells 3; ↓, decreased; ↑, increased.
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SUV39H1
HP1γ
SUV39H2
TRF1
SUV4-20H1
RB1
TRF2 RBL1 HP1α HP1γ HP1α HP1β HP1α
RBL2 Me Me Me Me Me Me Me triM H3-K9
TERT Me
Me Me Me Me
TERC
Me Me Me Me Me Me Me Me Me Me 3′OH
DKC1
triM H4-K20 Me Me Me Me Me
Restricted access of
telomerase/telomere-
SUV39H deficiency RB1 family loss elongating activities
Cancer to telomeres
HP1γ
SUV4-20H1
HP1α HP1γ HP1α HP1α
HP1β HP1β HP1β
Me Me Me Me Me Me Me
Me Me Me Me
Me Me Me Me
3′OH 3′OH
↓ Di- and trimethylation ↓ Trimethylation
of H3-K9 of H4-K20
↓ HP1α, HP1γ
↓ Trimethylation
of H4-K20? Telomerase/telomere- Telomerase/telomere-
↑ TRF1 elongating activities elongating activities
Abnormally long telomeres; altered binding of telomeric proteins
(e.g. TRF1 in SUV39-deficiency); telomere position effects?
Figure 2 | Epigenetic regulation of telomeric chromatin and implications for disease. Telomeres are bound by
nucleosome arrays, which contain histones that carry modifications that are characteristic of constitutive heterochromatin. The
suppressor of variegation 3–9 homologue (SUV39H) histone methyltransferases (HMTases) are required for the trimethylation
(triM) of H3-K9 (histone 3 at lysine 9) at telomeres, which efficiently recruits heterochromatin protein 1 (HP1) isoforms (HP1α,
HP1β and HP1γ) to these regions. HP1 recruits the suppressor of variegation 4-20 homologue (SUV4-20H) HMTases, which
trimethylate H4-K20 (histone 4 at lysine 20). The retinoblastoma (RB) family of proteins are important for this last step of
telomeric chromatin assembly, and a direct interaction between the SUV4-20H HMTases and the RB-family proteins has been
demonstrated in vitro. In the absence of the SUV4-20H HMTases there is a marked decrease in trimethylation of H3-K9, which is
coincidental with an increase (↑) in monomethylation and a decrease (↓) in the binding of HP1 proteins. These changes in
epigenetic marks are accompanied by abnormally elongated telomeres and an increased binding of the telomere repeat binding
factor 1 (TRF1) protein. Finally, a loss of H4-K20 trimethylation at telomeres as consequence of decreased HP1 binding is also
likely, although this possibility has not been formally demonstrated. In the absence of the RB family of proteins (some of which
are altered in human tumours), there is a marked loss of trimethylated H4-K20, which also results in abnormally elongated
telomeres. These findings indicate that the different epigenetic modifications at telomeres contribute to a ‘closed’ or ‘silenced’
chromatin state, which might regulate the access of telomerase and other telomere-elongating activities to telomeres. In
addition, epigenetic modifications at telomeres and changes in telomere length might regulate the binding of telomere-repeat
HETEROCHROMATIN binding factors (for example, TRF1), as well as the so-called telomere position effect or the transcriptional controls of genes
Chromosomal material that is located near telomeres. DKC1, dyskeratosis congenita 1, dyskerin; Me, methylated; RBL1/2, retinoblastoma-like 1 and 2;
tightly coiled and inactive in TRF2, telomere repeat binding factor 2; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase.
terms of gene expression.
SATELLITE REPEATS constitutive HETEROCHROMATIN8,9 (FIG. 2; TABLE 1. This at lysine 20 (H4-K20), histone modifications that are
DNA that contains many
tandem repeats of a short basic
indicates a potential higher-order level of control of carried out by the suppressor of variegation 3-9 homo-
repeating unit. Both the major telomere length and structure, which might have logue (SUV39H) and suppressor of variegation 4-20
and minor satellite repeats are important implications for human disease. homologue (SUV4-20H) histone methyltransferases
located at pericentric Constitutive heterochromatin is found at transcrip- (HMTases), respectively8–11 (FIG. 2; TABLE 1.
heterochromatin.
tionally inactive ‘silenced’ genomic regions of repetitive More recently, the RETINOBLASTOMA FAMILY of proteins
RETINOBLASTOMA PROTEINS DNA, such as pericentric SATELLITE REPEATS and telomeres. (retinoblastoma protein 1 (RB1) and retinoblastoma-
These are a family of tumour Similar to pericentric chromatin, telomeres are enriched like 1/2 (RBL1 and RBL2)), among which RB1 is
supressor proteins that share a for binding of the heterochromatin protein 1 (HP1) iso- frequently mutated in human cancer, have been
similar structure and function. forms HP1α (which is also known as chromobox protein demonstrated to be required for the trimethylation
Mutations in RB1 have been
associated with retinoblastoma,
homologue 5; CBX5), HP1β and HP1γ (FIG. 2; TABLE 1. of H4-K20 at both telomeres and centromeres9. In
a malignant eye tumour in They also contain high levels of histone 3 trimethyl- the absence of the RB-family proteins, this histone
children. ated at lysine 9 (H3-K9) and histone 4 trimethylated modification is rapidly lost. Indeed, these proteins
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can interact directly with the SUV4-20H HMTases, Telomere-binding proteins and human disease
providing a mechanism by which the RB family influ- Several of the proteins that bind to telomeres are
ences the assembly of both telomeric and pericentric implicated in disease conditions (FIG. 1c).
heterochromatin9 (FIG. 2). Interestingly, centromeres are
fundamental for chromosome segregation during cell The TRF1 and TRF2 complexes. A number of proteins
division and telomeres are essential to protect chro- that bind telomeric repeats, such as the TRF1 and TRF2
mosome ends from aberrant chromosomal rearrange- complexes mentioned above, regulate telomere length
ments2. Therefore, these results indicate a novel role and function1,19 (FIG. 1; TABLE 1. TRF1 forms a multi-
for the RB-family proteins in both chromosome seg- protein complex that contains the TRF1-interacting
regation and telomere-length control, in addition to its nuclear factor 2 (TIN2, also know as TINF1); the
more established role in controlling proliferation. TANK1 and TANK2 (tankyrase 1 and 2) poly(ADP)-
ribosylases; protection of telomeres 1 (POT1); the
Implications for telomere regulation. The different repressor/activator protein 1 (RAP1, also known
activities that remodel telomeric chromatin might be as TERF2IP); POT1 and TIN2 organizing protein
involved in higher-order control of telomere length and (PTOP, also known as adrenocortical dysplasia homo-
function. Indeed, mice that lack both the SUV39H1 logue (ACD)); and TRF2 (through its interaction with
and SUV39H2 HMTases have decreased di- and tri- TIN2) REF. 19 (FIG. 1C). TIN2 modulates the TANK1-
methylation of H3-K9, increased mono-methylation dependent poly(ADP)-ribosylation of TRF1, which
of H3-K9, and loss of HP1 binding at telomeres, which alters TRF1 binding to TTAGGG repeats. This is in
coincides with aberrant telomere elongation and altered turn thought to control telomere length by regulating
TRF1 binding8 (FIG. 2). Similarly, loss of RB-family pro- the access of telomerase to the telomere19. The TRF1
teins leads to the abnormal elongation of telomeres9,12. complex also controls telomere length through the
These findings indicate that loss of heterochromatic single-stranded telomere-binding POT1 protein and its
features at telomeres might lead to a less compact interacting PTOP protein, both of which are thought to
chromatin state, which in turn can result in abnormal regulate the access of telomerase to telomeres19.
telomere elongation owing to an increased access of The role of TRF1 seems to go beyond telomere
telomerase or other telomere-elongating activities to regulation. Mice that carry a targeted deletion of Trf1
the telomere (FIG. 2). do not show telomere-length defects or loss of telomere
Altered telomere structure and abnormal telomere protection20 TABLE 1, possibly due to compensation of
length might influence the transcriptional silencing of TRF1 function by TRF1-interacting proteins, although
genes that are located at the neighbouring subtelomeric this remains to be proved. However, this deletion
regions. This phenomenon is known as the telomere causes embryonic lethality. Interestingly, the TRF1-
position effect, and occurs in both yeast and mamma- regulatory protein TANK1 is essential for the sepa-
lian cells13–15, with profound effects on gene-expression ration of the telomeres of sister chromatids during
patterns. In mammalian cells, telomere elongation mitosis21, which indicates a role for this protein in cell
owing to telomerase reintroduction leads to transcrip- division. This could explain the lethality of Trf1 mice
tional repression of a reporter gene that is located near in the absence of telomere defects. Similarly, mice that
a telomere14. This effect is thought to result from the are deficient for TIN2 die as embryos, independently
induction of a repressive or more compact chromatin of telomere-length maintenance and telomerase activ-
state at telomeres that also affects nearby regions. ity22. Interestingly, TIN2 co-localizes to non-telomeric
Similarly, agents that alter chromatin structure, such heterochromatin domains through its interaction with
as the histone deacetylase inhibitor trichostatin A, HP1γ REF. 23, which indicates a putative role for this
increase the expression of reporter genes that are protein in heterochromatin assembly.
located near telomeres14,15, presumably through the In addition, the expression of TRF1, TRF2, TIN2,
induction of a more ‘relaxed’ chromatin state. POT1 and TANK1 is altered in some human tumour
Importantly, as telomere length can be epige- types24–28 (FIG. 1C; TABLE 1. The precise mechanism by
netically regulated by chromatin modifications, it which these proteins might contribute to tumorigenesis
is possible that the variable restoration of telomere remains unknown. It will be interesting to determine
length in cloned animals might be the consequence whether defects in any of these proteins have a role in
of epigenetic errors, especially as epigenetic modi- age-related diseases, a question that has not yet been
fications are not transmitted faithfully in clones16,17. addressed, due in part to a lack of viable mouse models.
Similarly, human syndromes that are characterized by
epigenetic defects, such as RETT SYNDROME18, might also TRF2 and DNA repair. The TRF2 complex has a funda-
RETT SYNDROME
be characterized by abnormal telomere-length regu- mental role in protecting the telomeric single-stranded
An X-linked dominant
neurological disorder that lation. This might contribute to disease pathology, G-rich overhang from degradation and from DNA
affects girls only and is one although this possibility has not yet been explored. repair activities, thereby preventing telomere end-to-
of the most common causes of Future studies warrant the complete identification end fusions19. Interestingly, a number of DNA repair
mental retardation in females. and characterization of the epigenetic modifications proteins that are involved in several repair pathways
Rett syndrome is due to a
mutation in the MECP2 gene
that regulate telomere structure and length for a bet- localize to telomeres19,29–36 (TABLE 1), and some of them
(methyl-CpG-binding ter understanding of telomere regulation and its role do so through a direct interaction with TRF2 REF. 19
protein 2). in human disease. (FIG. 1C; TABLE 1.
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Box 1 | Telomerase, telomere length and ageing Many TRF2-interacting telomeric proteins are
mutated in human chromosomal instability syndromes,
Telomeres undergo which are characterized by premature ageing, increased
characteristic length Germ Somatic Premature ageing susceptibility to cancer and shortening of telomeres to
changes over time in line cells syndromes
below the critical length (FIG. 1C; TABLE 1. In the past few
normal somatic and
+ years, it has become apparent that an important com-
germline cells, and in
Telomere length
premature ageing ponent of the pathobiology of these premature ageing
syndromes. In contrast to diseases is the presence of critically short telomeres,
germ cells, which have high which are likely to synergize with the corresponding
–
telomerase activity DNA repair defects, leading to disease presentation. In
Health
(indicated by the plus particular, mutations in Nijmegen breakage syndrome 1
symbol on the graph) and
Disease
(NBS1; also known as nibrin (NBN)) and meiotic
maintain telomere length recombination 11 (MRE11) — two components of the
with age, most somatic Age MRE11 complex that have a central role in double-
cells show progressive stranded-break repair — are responsible for the human
telomere shortening owing to low or absent telomerase activity (indicated by the minus Nijmegen breakage syndrome49 and the Ataxia-tel-
symbol on the graph). This progressive telomere loss eventually leads to critically short angiectasia-like disorder50 (ATLD) respectively (FIG. 1C;
telomeres, which triggers a DNA damage response that results in chromosomal end-to- TABLE 1. Similarly, the Werner syndrome (WRN) and
end fusions or cell arrest and apoptosis. This loss of cell viability associated with
Bloom syndrome (BLM) genes, which are involved in
telomere shortening is thought to contribute to the onset of degenerative diseases that
crosslink repair, are mutated in the Werner and Bloom
occur during human ageing. In addition, several human premature ageing syndromes
show an accelerated rate of telomere shortening, therefore resulting in an early onset of human syndromes, respectively51 (FIG. 1C; TABLE 1. The
ageing-related pathologies. Examples of these diseases are listed below. XPF/ERCC1 (excision repair cross-complementing 1)
nuclease, which is involved in the nucleotide excision
Premature ageing syndromes with short telomeres repair pathway for repair of UV-induced lesions and
The genes that are mutated in these syndromes are indicated in brackets. Ataxia
in DNA crosslink repair, is mutated in the human
telangiectasia (ATM); Werner syndrome (WRN); Bloom syndrome (BLM); dyskeratosis
congenita (DKC1, Terc); aplastic anaemia (Terc, Tert); Fanconi anaemia (FANC genes);
xeroderma pigmentosum syndrome, which shows
Nijmegen breakage syndrome (NBS); and ataxia telangiectasia-like disorder (MRE11). hypersensitivity to UV light, premature ageing and
increased incidence of skin cancer52. Finally, mutations
Ageing-related pathologies with short telomeres that affect the ATM protein are responsible for the
Heart failure; immunosenescence (infections); digestive tract atrophies (ulcers);
human syndrome ataxia telangiectasia, which is also
infertility; reduced viability of stem cells; reduced angiogenic potential; reduced
characterized by chromosomal instability, radiosensi-
wound-healing; and loss of body mass.
tivity, premature ageing defects and increased incidence
of cancer53 (FIG. 1C; TABLE 1. Other DNA repair proteins
Some of the DNA repair proteins that are present at with an impact on telomere protection and telomere-
telomeres have a direct role in regulating telomere length length regulation, such as proteins that are involved in
and telomere protection32–42 TABLE 1, which indicates an homologous recombination (HR), non-homologous
interplay between DNA repair and telomere function. end joining and mismatch repair (MMR) are altered in
In turn, telomere-binding proteins and telomere length various types of human tumour42,54,55 (FIG. 1C; TABLE 1.
might influence DNA damage repair in non-telomeric The fact that many of the TRF2-interacting proteins
regions. TRF2 rapidly localizes to laser-induced sites of are responsible for human chromosomal instabil-
DNA damage and has been shown to block the ataxia ity syndromes indicates that TRF2 itself might also
telangiectasia mutated (ATM)-dependent DNA damage have an important role in human disease. TRF2 is
response43,44, although it remains to be demonstrated overexpressed in a number of human tumours (lung,
that TRF2 directly affects DNA repair or sensitivity to liver and gastric cancer), indicating a role for TRF2 in
DNA damage. In addition, lack of telomere protection, tumorigenesis24,27,28 (FIG. 1C; TABLE 1. The exploration of
due to either a critical loss of TTAGGG repeats or loss a putative role of TRF2 in ageing, however, awaits the
of TRF2 function, triggers a DNA damage response that development of appropriate mouse models.
involves the same signalling cascade that is activated by
double-stranded breaks, including phosphorylation of Telomerase, telomere elongation and disease
γ-H2AX and ATM, transformation-related protein 53 Telomerase and other telomere-elongating activities.
(p53) stabilization, and p53-binding protein 1 (53BP1) In contrast to germ cells, most normal human somatic
binding45–47. Short or dysfunctional telomeres can lead tissues and adult stem cells do not express sufficient
to end-to-end telomere fusions that are mediated by the telomerase to maintain telomere length indefinitely,
non-homologous end-joining machinery 40,41, and can and therefore undergo telomere attrition with age56
re-join with double-stranded breaks at non-telomeric BOX 1. This telomere shortening can eventually lead
sites, therefore interfering with their proper repair and to critically short or unprotected telomeres and loss of
leading to chromosomal translocations48. Consistent organismal viability, indicating an important role for
with these findings, both telomerase-deficient mice telomerase activity and telomere length in the patho-
and cells that have critically short telomeres are hyper- biology of human disease BOX 1. Indeed, many human
sensitive to ionizing radiation and other genotoxic diseases of different origins that are associated with
agents48. ageing, as well as late stages of cancer, are characterized
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Table 2 | Mouse models of telomerase and telomere length in human disease
Genotype Ageing phenotype Cancer phenotype References
Models of telomerase abrogation
Terc–/– Defects in neural tube closure, hypogonadism, infertility, immunosenescence, Reduced incidence 64–74
intestinal atrophy, alopecia, hair greying, heart dysfunction, bone marrow aplasia, of cancer
kidney dysfunction, defective bone marrow and neural stem-cell proliferation
Terc–/–/(p16/p19ARF)–/– Not studied Reduced incidence 79
of cancer
Terc–/–/Atm–/– Ataxia telangiectasia-like ageing pathologies including neurological defects Reduced incidence 102,105
of cancer
Terc–/–/DNA-PKcs–/– Accelerated ageing Reduced incidence 41,109
of cancer
Terc–/–/Ku86–/– Accelerated ageing Reduced incidence 40,109
of cancer
Terc–/–/Blm–/– Bloom syndrome-like ageing pathologies including bone loss and reduced body Not studied 101,106
weight
Terc–/–/Wrn–/– Werner syndrome-like ageing pathologies including bone loss, type II diabetes Not studied 100,104
and cataracts
Terc–/–/Apcmin Not studied Reduced incidence 78
of cancer
Terc–/–/p53+/– Not studied Increased incidence 77
of cancer
Terc–/–/ApoE–/– Protection from atherosclerosis Not studied 75
Terc–/–/Parp1–/– Slightly accelerated ageing Reduced incidence 109
of cancer
Models of telomerase overexpression
K5-Tert Less kidney and germ-line dysfunction Increased incidence 80–82,86
of cancer
Actin-Tert Not studied Increased incidence 83
of cancer
Lck-Tert Not studied Increased incidence 84
of cancer
α Mhc-Tert Less heart dysfunction Not studied 85
Apcmin, adenomatous polyposis coli, min (multiple intestinal neoplasia) allele; ApoE, apolipoprotein E; Atm, ataxia telangiectasia mutated; Blm, Bloom syndrome;
DNA-PKcs, DNA-dependent protein kinase catalytic subunit; Ku86, Ku antigen protein 86; K5, keratin 5; Lck, lymphocyte-specific protein tyrosine kinase; Mhc, major
histocompatibility complex; Parp1, poly(ADP-ribose) polymerase family 1; p16/p19ARF, p16/p19 alternative reading frame; p53, p53 tumour-suppressor protein;
Terc, telomerase RNA component; Tert, telomerase reverse transcriptase; Wrn, Werner syndrome.
by the presence of short telomeres56–58, probably reflect- significant changes in telomerase activity, highlighting
ing their long proliferative history BOX 1. In addition them as potential regulators of ALT, although direct
to the role of telomerase in preventing telomere deg- demonstration for this is still required.
radation below a critical length, telomerase can also
increase survival even at stages when telomeres are Mouse models of telomerase and telomere-length
sufficiently long, therefore conferring another growth defects. The telomerase-deficient mouse model has
advantage59. been instrumental in demonstrating the impact of
Some immortal human cell lines and tumours that short telomeres in the context of the whole organism.
lack telomerase activity are still able to maintain or Telomerase-deficient mice were first generated by
elongate their telomeres by telomerase-independent elimination of the mouse Terc gene63,64. The long-term
mechanisms, a phenomenon known as ALT (alterna- viability of the Terc–/– mouse strain is severely com-
tive lengthening of telomeres)60. In yeast and mammals, promised, and only a limited number of generations
the HR-repair pathway has been implicated in ALT61,62. can be derived, due to infertility and the progres-
In addition, activities that regulate HR (such as the sive ANTICIPATION of pathologies that are associated
MMR genes, the DNA repair proteins RAD54 and with loss of telomeric repeats64–73. These patholo-
RAD51D, and the X-ray repair complementing defec- gies include loss of fertility, heart failure, immuno-
ANTICIPATION
tive repair in Chinese hamster cells 3 protein, XRCC3 senescence-related diseases, various tissue atrophies
A phenomenon in which a
REFS 42,3436) or proteins that modify the state of the and decreased tissue regeneration (of the digestive
genetic disease appears earlier
in the lifetime of an individual telomeric chromatin (SUV39H HMTases and the RB system, skin and haematopoietic system) TABLE 2.
with each successive generation. family)8,9,12 can affect telomere length in the absence of Interestingly, these pathologies recapitulate disease
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states of different aetiology that also occur during a
human ageing, which are characterized by cells
with short telomeres, possibly as the consequence Normal Early Late tumour
tissue tumour metastasis
of excessive proliferation. The telomerase-deficient
Telomere length
mouse is considered to be a promising model to
study telomere-driven ageing. –
–
Interestingly, the pathologies that occur in the
telomerase-deficient mouse model are accompanied +
by a reduction in proliferative potential or increased Viable
apoptosis in the affected tissues. These effects coincide
Apoptosis/cell-cycle arrest/chromosomal instability
with upregulation of the tumour-suppressor gene p53
REFS 72,74, in agreement with the idea that short telo- Time
meres trigger a DNA damage response45,46. By contrast,
b
those human diseases associated with ageing that are
characterized by increased proliferation, such as cancer
or atherosclerosis, are not reproduced in the telomerase-
deficient mouse74,75 TABLE 2, which indicates that
development of these diseases requires further altera-
tions to bypass the DNA damage signal that is triggered
by short telomeres.
These findings indicate that a minimum telomere Normal tissue Apoptosis/
length is necessary to maintain normal tissue homeo- cell-cycle arrest
Telomerase-negative
stasis in the mouse, and predict that the telomere tumour cell Distant
shortening that occurs with age in humans and is metastasis
Telomerase-positive
associated with various disease states might also lead to tumour cell
similar pathologies. This idea is supported by the fact
that reintroduction of the telomerase Terc gene in telo- Figure 3 | Telomerase and telomere length in
merase-deficient mice with inherited short telomeres tumorigenesis. a | Changes in telomere length over time
prevents further telomere shortening, chromosomal during tumour progression, compared with changes in normal
tissue. Tumours generally have shorter telomeres than the
instability and loss of organismal viability76. surrounding normal tissue, owing to the fact that they have
In addition to the role of telomere shortening in had a longer proliferative history in the absence of telomerase
organismal ageing, short telomeres have also been pro- activity. This telomere shortening could eventually lead to
posed to mediate tumour suppression by preventing increased cell death and loss of cell viability within the tumour.
the proliferation of cells with telomere dysfunction, However, telomerase is reactivated in more than 90% of all
which might also carry chromosomal aberrations57 types of human tumour, thereby rescuing short telomeres and
perpetuating cells with short telomeres and high
(FIG. 3). In particular, late-stage human cancers gen-
chromosomal instability. Similarly, most metastases also
erally have shorter telomeres than the surrounding contain telomerase-positive cells, which indicates that
normal tissue owing to a longer proliferative history. telomerase is required to sustain their growth. The fact that
This progressive telomere shortening in the absence cancer cells have shorter telomeres than normal cells,
of telomerase could eventually trigger a DNA damage together with the fact that cancer growth seems to depend on
response, thereby impairing cell division and increas- telomerase reactivation, indicates that therapeutic strategies
that are aimed at inhibiting telomerase will preferentially kill
ing apoptosis within the tumour (FIG. 3). However, in
tumour cells and have no toxicity on normal cells. The
the absence of the appropriate checkpoints (for exam- presence or absence of telomerase activity is indicated by the
ple, p53 deficiency), short telomeres can contribute to plus symbol and minus symbol respectively. b | The
the high chromosomal instability that is characteristic composition of cells in a tumour over the same time-frame.
of human tumours57. Further selection for tumour
cells that have reactivated telomerase (>90% of human
cancers) would then guarantee their indefinite growth main tumour-suppressor pathways77–79 TABLE 2. As an
potential by rescuing short telomeres and preventing exception to this, telomerase deficiency and short telo-
58,77
MITOTIC CATASTROPHE (FIG. 3). meres, in the context of p53-heterozygous mice, lead
Telomerase knockout mice have been instru- to increased numbers of epithelial tumours with high
mental in dissecting these putative roles of telomeres levels of chromosomal instability, again indicating that
and telomerase in tumorigenesis. These models have p53 is an important mediator of the cellular response to
demonstrated that short telomeres, in the absence of short telomeres77,78.
telomerase, function as potent tumour suppressors, Mice that overexpress Tert in adult tissues also dem-
MITOTIC CATASTROPHE which is coincident with p53 upregulation74. Similarly, onstrate an impact of telomerase in both cancer and
The loss of cell viability that tumorigenesis is reduced also in mice that are simul- ageing that seems to be independent of telomere length
results from the attempted taneously deficient in both telomerase and tumour- TABLE 2. In particular, mice that overexpress Tert under
aberrant chromosome
segregation in the presence of
suppressor genes other than p53 — such as p19ARF, the control of various promoters are more susceptible to
severe cellular damage (for p16 or Apc . This supports the idea that short telomeres developing tumours as they age than wild-type controls
example, short telomeres). suppress carcinogenesis even in the absence of the are80–84 TABLE 2. Interestingly, Tert transgenic mice also
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show increased protection against certain age-related death. However, an important difference between
pathologies, such as kidney dysfunction and infertility the two is the fact that DC patients show an elevated
in the case of mice that overexpress Tert in stratified incidence of spontaneous cancer, whereas telomerase-
epithelia, under the control of the keratin 5 promoter deficient mice have an increased resistance to
(K5–TERT mice), or heart dysfunction in the case of cancer74,78,79.
mice that overexpress Tert in cardiac muscle, under the An explanation for this discrepancy might be pro-
control of the α-myosin heavy chain promoter (major vided by the fact that DC patients still have telomerase
histocompatibility complex (MHC)–TERT mice)82–85 activity, although at lower levels than in healthy indi-
TABLE 2. The mechanisms that underlie these effects viduals, and this could be aberrantly upregulated during
of Tert on cancer and ageing are largely unknown, tumorigenesis. By contrast, Terc–/– mice are telomerase
although they seem to require the telomerase RNA deficient. Therefore, DC is a human premature ageing
component that is encoded by Terc86. These findings syndrome that closely, but not completely, recapitu-
indicate that telomerase might have a significant effect lates the phenotype of the telomerase-deficient mouse
on cancer and ageing, even in the stages at which model. Similarly to telomerase-deficient mice, human
telomeres are long enough to maintain viability. DC is characterized by disease anticipation in affected
progeny, which demonstrates that short telomeres
Telomerase defects and short telomeres in human directly contribute to disease presentation95. In addi-
disease. The fact that short telomeres can trigger tion, several patients that were diagnosed with aplastic
a rapid loss of cell viability in telomerase-deficient anaemia also carry mutations in the telomerase Terc and
mouse indicates a putative role of defects in telomeres Tert genes, resulting in accelerated telomere shortening
and telomerase in the pathobiology of human disease. and premature death96,97 BOX 1; FIG. 1C; TABLE 1.
As mentioned above, short telomeres are characteristic In addition to DC and aplastic anaemia patients,
of human diseases of various origins that are associ- who have defective telomerase activity and short telo-
ated with ageing, such as heart disease87, ulcerative meres, several other human premature ageing syn-
colitis88, liver cirrhosis89 and atherosclerosis90, as well dromes are also characterized by an accelerated rate
as several premature ageing syndromes BOX 1; FIG. 1C; of telomere loss and chromosomal instability BOX 1.
TABLE 1. In addition, a correlation between telomere Interestingly, these diseases are produced by mutations
length and risk of death from heart disease or infec- in DNA repair proteins such as NBS1, MRE11, WRN,
tions has been recently observed91, further indicating BLM, ATM and FANC (Fanconi anaemia complemen-
that telomere length might directly contribute to such tation group proteins)49–51,98,99 BOX 1; TABLE 1, many of
diseases. Finally, factors that are considered to accel- which also have a role at telomeres, as discussed in a
erate ageing and to be a risk for premature death, previous section. Strikingly, mice that are deficient
such as perceived stress, can also negatively impact for these proteins do not recapitulate the full-blown
on telomerase-activity levels and telomere length in human pathology and, in particular, they do not faith-
affected individuals92. fully reproduce premature ageing pathologies100–103.
Several human premature ageing syndromes are A possible explanation for this is the fact that mice
characterized by a faster rate of telomere attrition have longer telomeres and higher levels of TERT than
with age, and these have provided important insights humans and, therefore, a contribution of short telo-
into the consequences of telomere loss BOX 1; FIG. 1C; meres to the pathobiology of the disease is also lacking
TABLE 1 . One of these syndromes is dyskeratosis in these different mouse models.
congenita (DC). DC patients carry mutations in com- In support of this idea, the ageing pathologies associ-
ponents of the telomerase complex, which result in ated with the Werner, Bloom and ATM syndromes have
decreased telomerase stability and shorter telomeres93. been modelled in mice only when in combination with
These mutations affect either the Terc gene (patients telomerase deficiency and short telomeres in the context
with the autosomal dominant DC variant)94,95 , or of the telomerase-deficient mouse model104–108 TABLE 2.
the dyskeratosis congenita 1, dyskerin gene (DKC1) This demonstrates that short telomeres contribute to
(patients with the X-linked form of the disease), which the pathobiology of these premature ageing diseases.
encodes a protein that is involved in Terc stability and Similarly, mice that are deficient in FANC genes have
93
snoRNA processing . Both mutations result in decreased normal telomeres and do not fully reproduce the
telomerase activity and shorter telomeres compared human disease phenotype107, which suggests that short
with healthy individuals93–95. telomeres in Fanconi anaemia patients are responsible
snoRNA Strikingly, DC patients show increased chromo- for a large part of the pathology. Also, in agreement with
Small nucleolar RNAs. The somal instability with age, consistent with a faster rate the idea that short telomeres synergize with some DNA
functions of these snoRNAs
of telomere loss, which indicates that DC might be a repair deficiencies in accelerating organismal ageing,
include RNA cleavage reactions,
as well as specifying sites of chromosomal instability syndrome that is produced mice that are deficient in both telomerase and either
ribose methylation and by a defect in telomerase activity and the proper Ku86 autoantigen-related protein 1 (KU86; also known
pseudouridylation. Mutations maintenance of telomeres. DC patients develop many as XRCC5) or DNA-dependent protein kinase catalytic
in DKC1 (dyskeratosis of the pathologies shown for the telomerase-deficient subunit (DNA-PKcs) activities, but not in poly(ADP-
congenita 1, dyskerin) result
in defective pseudouridylation
mouse model, such as short stature, hypogonadism ribose) polymerase family 1 (PARP1), show an accel-
of the H/ACA box class of and infertility, defects of the skin and the haemato- eration of the ageing phenotypes that are associated
snoRNAs. poietic system, bone marrow failure, and premature with telomerase deficiency109 TABLE 2.
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Therapeutic approaches viability during the human lifetime, therefore providing
Establishing the role of telomeres and telomerase in a window of opportunity for intervention (FIG. 3).
human disease has been important for the design
of appropriate therapeutic strategies. The fact that Conclusions and future directions
diseases that are associated with human ageing and Since first proposed in 1990 by Harley et al. 56 ,
premature ageing syndromes are characterized by mounting evidence indicates that telomere shorten-
short telomeres, together with observations from the ing with increasing age is a biological determinant in
Terc-knockout mouse model that demonstrate that the pathobiology of human disease. Human diseases
short telomeres contribute to these different patholo- that are associated with ageing, including cancer and
gies, indicates the therapeutic potential for strategies premature ageing syndromes, are characterized by
that are based on temporary telomerase reactivation. short telomeres at the time of disease presentation,
Therapeutic agents that could be designed to do this which in turn can actively contribute to loss of cell
would preferentially target those cell types that nor- viability.
mally divide to maintain organ homeostasis, such as The role of decreased telomerase function in
stem cells, which, although telomerase-proficient, do premature ageing syndromes highlights the fact that
not have sufficient telomerase activity to maintain telomerase activity is tightly regulated to maintain
telomere length over time. Germ-line reintroduction sufficient telomeric repeats, and therefore prolifera-
of telomerase extends inherited short telomeres in tive potential, to maintain tissue homeostasis during
mouse models and prevents end-to-end fusions and a human lifetime. If telomerase activity levels are con-
pathologies that are associated with short telomeres, stitutively decreased, such as in diseases with muta-
such as bone marrow aplasia, atrophy of the intestinal tions in the telomerase genes, this is accompanied by
epithelium, hypogonadism and infertility76. shorter telomeres, premature loss of organismal fitness
Similarly, telomerase reactivation could prevent and decreased lifespan. It is important to consider that
critical telomere shortening and associated patholo- these diseases are likely to specifically affect those cell
gies in those premature ageing syndromes that are populations that normally have telomerase activity
characterized by a faster rate of telomere loss, as well in the adult organism, such as stem cells, which need
as in age-associated diseases. In this regard, both the telomerase to maintain tissue regeneration. It will be
telomere-length defect and the DNA repair deficiency important to confirm this possibility in future stud-
that are characteristic of the human Nijmegen breakage ies by determining the effect of telomerase deficiency
syndrome can be corrected by simultaneous reintro- and telomere shortening in different adult stem-cell
duction of NBS1 and the telomerase TERT subunit in populations.
cultured cells49. Similarly, reintroduction of telomerase All the human premature ageing syndromes that
in Werner syndrome cells can correct short telomeres show a faster rate of telomere loss, as well as telomerase-
and extend the lifespan of the cells51. deficient mice, are also characterized by showing high
By contrast, the fact that the vast majority of human levels of chromosomal instability, which indicates that
tumours seem to depend on telomerase reactivation to short telomeres cause ageing by leading to increased
prevent critical telomere loss and to divide indefinitely DNA damage. In this context, short telomeres in
indicates that telomerase inhibition could be an effec- tumours that have aberrantly upregulated telomerase
tive way to abolish tumour growth57,59. An increasing are likely to be responsible for part of the chromosomal
number of therapeutic strategies that are based on instability of the tumour, although this awaits formal
targeting telomerase in cancer have been developed demonstration.
over the past few years, which include pharmacologi- In addition to telomerase activity, it is likely that
cal inhibitors of the enzyme, as well as immunotherapy many of the proteins that are important in regulating
strategies57,110. Many of these strategies are based on telomere length and function — such as the telomere
triggering critical shortening of telomeres and loss repeat binding factors, proteins involved in DNA repair
of cell viability. Interestingly, short telomeres, in the and activities that participate in the assembly of the telo-
context of telomerase deficiency, are likely to function meric heterochromatin — will also have an important
synergistically with anticancer therapies that are based role in human disease as they can regulate the action
on genotoxic agents, because telomere dysfunction of telomerase at telomeres. In the future, the genera-
results in hypersensitivity to DNA damaging agents66. tion of viable mouse models that are deficient for these
The fact that telomerase deficiency only results different telomere-binding proteins will be needed to
in loss of organismal viability when telomeres reach demonstrate their role in cancer and ageing.
a critically short length is an important point when In conclusion, a clear picture is emerging in which
considering the possible secondary effects of these telomerase activity and telomere length have a crucial
therapies. In particular, this predicts that putative anti- role in human disease. Studies of human ageing syn-
cancer therapies that are based on temporary telomer- dromes and transgenic mouse models have allowed an
ase inhibition will only trigger loss of viability in those exploration of the balance between the need to main-
cells with short telomeres that depend on telomerase tain telomere length and the need to prevent aberrant
activity. Presumably, these include tumour cells, but telomere elongation, reconciling cancer and ageing
not healthy tissues, which generally lack telomerase as two different end points of pathological telomere
activity and have sufficiently long telomeres to maintain shortening.
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