The telosome/shelterin complex and its functions.

Abstract

The telomeres that cap the ends of eukaryotic chromosomes serve a dual role in protecting the chromosome ends and in intracellular signaling for regulating cell proliferation. A complex of six telomere-associated proteins has been identified--the telosome or shelterin complex--that is crucial for both the maintenance of telomere structure and its signaling functions.

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Genome B Bi io ol lo og gy y 2008, 9 9: :232
Review
T Th he e t te el lo os so om me e/ /s sh he el lt te er ri in n c co om mp pl le ex x a an nd d i it ts s f fu un nc ct ti io on ns s
Huawei Xin*, Dan Liu*†and Zhou Songyang*
Addresses: *Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Baylor Plaza,
Houston, TX 77030, USA. †Cell-Based Assay Screening Service Core, Baylor College of Medicine, Houston, TX 77030, USA.
Correspondence: Zhou Songyang. Email: songyang@bcm.edu
A Ab bs st tr ra ac ct t
The telomeres that cap the ends of eukaryotic chromosomes serve a dual role in protecting the
chromosome ends and in intracellular signaling for regulating cell proliferation. A complex of six
telomere-associated proteins has been identified - the telosome or shelterin complex - that is
crucial for both the maintenance of telomere structure and its signaling functions.
Published: 18 September 2008
Genome B Bi io ol lo og gy y 2008, 9 9: :232 (doi:10.1186/gb-2008-9-9-232)
The electronic version of this article is the complete one and can be
found online at http://genomebiology.com/2008/9/9/232
© 2008 BioMed Central Ltd
Telomeres are specialized structures at the ends of eukaryotic
chromosomes that help to maintain genome integrity in
eukaryotes by preventing chromosomal rearrangements or
chromosomes fusing to each other, and by enabling com-
plete replication of the ends of the linear DNA molecules.
Telomeric DNA is composed of a series of sequence repeats
and terminates in a 3’ single-stranded (ss) DNA overhang. At
each round of DNA replication the telomeric DNA becomes
shorter, but it can be regenerated by the enzyme telomerase,
an RNA-containing DNA polymerase. Both the double and
single-stranded telomeric DNA is bound and protected by
DNA-binding proteins that in turn associate with other
signaling proteins/complexes to achieve telomere-end
protection and length control. The length of telomeric DNA
is maintained by the enzyme telomerase, but in addition, six
telomere-associated proteins - TRF1, TRF2, POT1, RAP1,
TIN2 and TPP1 in mammalian cells - have been shown to
form a complex known as the telosome, or shelterin com-
plex, that is essential for telomere function [1-10]. Here we
will briefly review the composition of the telosome, its role in
telomere maintenance, and its connections with intracellular
signaling pathways.
Telomere repeat factor-1 (TRF1) and -2 (TRF2) are related
proteins that share a number of sequence and organizational
similarities, and along with protection of telomeres-1 (POT1),
they interact directly with telomeric DNA. RAP1 (the human
homolog of the yeast telomeric protein Rap1), TRF1-
interacting protein 2 (TIN2), and TPP1 (also known as
TINT1/PTOP/PIP1) associate with these DNA-binding
proteins to form the core telosome (Figure 1). Various sig-
naling pathways originate from these core telomeric proteins
and their subcomplexes, and from this it has been possible
to deduce a telomere ‘interactome’ [11]. In this interactome,
the telosome serves as the core building block, coordinating
protein-protein interactions and protein complex cross-talk
on the telomeres.
T TR RF F1 1 a an nd d T TR RF F2 2 a an nd d t th he ei ir r i in nt te er ra ac ct ti io on n n ne et tw wo or rk ks s
TRF1 and TRF2 each bind telomeric double stranded (ds)
DNA as homodimers, with dimerization mediated by the
TRF-homology (TRFH) domain [3,4,12]. TRF1 homodimers
are postulated to monitor telomere length, whereas TRF2
homodimers serve to stabilize telomeric loop (t-loop) forma-
tion and protect the telomere end (t-loops are structures that
appear to form as a result of the 3’ overhang invading the
duplex telomeric repeats). TRF1 and TRF2 interactions with
a number of proteins within the interactome have also been
mapped to their respective TRFH domains [13]. TRF1 has a
propensity for binding long tracts of dsDNA whereas TRF2
binds the ds/ssDNA junction [14]. Both TRF1 and TRF2
have carboxy-terminal Myb domains, which are essential for
binding directly to telomere duplex DNA [3,4].
Human TRF1 and TRF2 differ from each other at their
amino terminus, which comprises an acidic region in TRF1
and a basic region in TRF2. The function of these regions is

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poorly understood, although recent studies suggest that the
basic amino-terminal domain of TRF2 is important for
binding of the ds/ssDNA junction and for the supercoiling of
telomeric DNA, and may regulate the formation and stabili-
zation of the t-loop structure [15-17]. Deletion of the basic
region of TRF2 does not affect its targeting or binding to
telomeres in vivo; the overexpression of this truncated
protein does, however, lead to disruption of telomere end
protection and the induction of cellular senescence and apop-
tosis [18,19]. Overexpression of a TRF2 construct lacking
both the basic and the Myb domains leads to an increased
occurrence of chromosomal fusions and interchromosomal
bridging [20].
As illustrated in Figure 1, TRF1 and TRF2 also function as
protein-interaction hubs within the telomere signaling
network, interacting directly with the other members of the
telosome and with a diverse array of proteins and protein
complexes that are involved in the cell cycle and in DNA
repair and recombination, to maintain telomere structure
and length [2,21-28]. TRF1 has been postulated to modulate
the length of telomere repeats primarily via its interaction
with the telosome proteins TIN2, TPP1 and POT1, and with
PINX1, an inhibitor of telomerase [7,9,10, 29-37]. For
example, the direct interaction of TRF1 with PINX1 provides
a possible mechanism for how TRF1 could regulate telomere
length [34]. PINX1 may be recruited to the telomeres
through its interaction with TRF1 and negatively regulate
telomere length by directly inhibiting telomerase.
TIN2 was identified on the basis of its ability to interact with
TRF1 in yeast two-hybrid assays [30]. TIN2 is a key
component of the telosome, and associates with both TRF1
and TRF2 [1,38,39]. TRF1-TIN2 interaction occurs through
the TRFH domain and the TIN2 carboxy-terminal domain
[13,30]. TIN2 is a negative regulator of telomere length and
is essential for bringing together the DNA-binding proteins
within the telosome complex.
TPP1 interacts with both TIN2 and POT1, and is the link that
connects the activities of the dsDNA-binding TRF1 to those
of the ssDNA-binding POT1 [8-10]. POT1 binds ssDNA,
regulates telomere length, and helps to stabilize the T-loop
and protect the telomere end. TIN2 is the major TRF1-inter-
acting protein, and TPP1 is the major POT1-interacting protein,
so TPP1 links these two DNA-binding activities assembled
on the telomeres. The TRF1-TIN2-TPP1-POT1 association
illustrates an important path through which signals are
communicated along a telomere. The functions of POT1 and
TPP1 are discussed in more detail later.
In addition to the interactions described above, TRF1 can
associate with tankyrase, a protein with poly(ADP-ribose)
polymerase activity [33], end-binding protein 1 (EB1) [40],
the nucleolar protein nucleostemin [41], and the F-box
protein FBX4, which participates in protein ubiquitination
[42] (Figure 1). Human EB1 is able to interact with and
target the tumor suppressor protein adenomatous polyposis
coli (APC) to microtubules in a cell-cycle-dependent manner.
Tankyrase has been implicated in the control of spindle
structure [43] and sister-chromatid cohesion [44], and thus
through interactions with tankyrase and EB1, TRF1 could be
involved in cell-cycle dependent regulation of telomere
function. Levels of TRF1 protein can be controlled by tanky-
rase, FBX4 and nucleostemin [41,42,45]. TRF1 can be poly-
ADP ribosylated by tankyrases [33], which may lead to its
ubiquitination and subsequent degradation [45], while FBX4
is an E3 ligase specific for TRF1 ubiquitination via the Cul1-
containing SCF complex [42], which leads to proteasomal
TRF1 degradation. Nucleostemin enhances TRF1 degradation
by a ubiquitination-independent pathway [41].
Both TRF1 and TRF2 can be sumoylated by the SUMO ligase
MMS21, a component of the SMC5/6 complex, which is
involved in DNA repair and recombination [46]. A number
of human tumors and tumor cell lines have a telomerase-
independent mechanism for telomere elongation that
involves homologous recombination, and which is referred
to as ‘alternative lengthening of telomeres’ (ALT) [47]. As
demonstrated in cells that display ALT, sumoylation of TRF1
and TRF2 helps to promote the recruitment of telomeres to
intranuclear macromolecular complexes called APBs (the
equivalent of PML bodies in other cells) and promote
telomere lengthening through homologous recombination.
However, it remains to be determined whether TRF1 and
TRF2 are similarly modified in other cell types.
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Genome B Bi io ol lo og gy y 2008, 9 9: :232
F Fi ig gu ur re e 1 1
The telomere interactome. This diagram depicts most of the known
protein-protein interactions centered on telomeric proteins. The
telosome is shaded in blue. Lines indicate protein-protein interactions,
yellow dots indicate nodes and red dots indicate protein hubs.
Rad50
TANK
EB1
BLM
APOLLO
ERCC1
Ku70
Telomerase
RAD51D
WRN
PINX1
FBX4
PARP1/2
RIF-1
Dyskerin
complex
hnRNPs
TPP1
POT1
TIN2
TRF1
TRF2
DNA-PKcs
Histone
HP1
?
ATM
EST1
IRAP
Mcl-1
TAB182
CHK1
MDC1
SMG5-7
L22
hStau
TEP1
La
UPF1
NuMA
CHK2
p53
MDM2
SMC1
53BP1
Mre11
NBS1
Ku86
ORC1
RIF-1
UPF2
p23/p90
14-3-3
MKRN1
?
9-1-1
Sm
RAP1
MMS21
SMC5/6
complex
NS
?
?

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T TR RF F1 1 a an nd d T TR RF F2 2 a an nd d D DN NA A d da am ma ag ge e r re es sp po on ns se e p pa at th hw wa ay ys s
Both TRF1 and TRF2 are intimately linked with DNA
damage response pathways. The ss/dsDNA structure at the
telomere could be perceived by the cell as DNA damage,
and TRF1 and TRF2 appear to be part of the mechanism
that prevents a damage response being generated. TRF1
co-immunoprecipitates with the protein kinase ATM
(ataxia telangiectasia mutated), a sensor of DNA damage,
and can be phosphorylated by ATM both in vivo and in
vitro [48,49]. Phosphorylation of TRF1 by ATM leads to
impairment of TRF1’s capacity to interact with DNA [49],
and the expression of phosphorylation-site mutant TRF1
induces mitotic entry and apoptosis [40]. The MRN
complex, functioning together with ATM, is also important
for regulating TRF1 activity [49]. The MRN complex
appears to be required for ATM-mediated phosphorylation
of TRF1.
Numerous studies have demonstrated the essential role of
TRF2 in telomere end protection. In addition to ATM,
TRF2 also recruits a variety of other DNA damage-sensing
and DNA repair proteins to the telomere, such as nucleases
ERCC1/XPF [50] and Apollo [51,52]; the DNA repair MRN
complex [53,54]; the helicases BLM [55] and WRN [55];
Ku70/Ku86 [54,56], and poly-ADP ribose polymerases
PARP1/2 [54,57,58] (Figure 1). The recruitment of these
proteins presumably functions to prevent telomere ends
being recognized as DNA breaks or to sensitize the cell to
damage to the telomeres. It is equally possible that TRF2-
associated complexes of ‘damage proteins’ are different in
composition or modification state from the canonical
complexes involved in repairing radiation-induced double-
strand DNA breaks, given that the TRF2-based complexes
normally do not evoke a cell-cycle checkpoint response
[59,60]. It should be noted that TRF2 has been shown to
localize to sites of high-energy radiation-induced DNA
damage outside the telomeres [61,62]. Therefore, the asso-
ciation of TRF2 with DNA damage response proteins may
have a role beyond telomere protection.
TRF2 mediates its protective function partly through
heterodimerization with the telosome component RAP1,
which contains a Myb domain [6]. In human cells,
inhibition of RAP1 or dominant-negative expression of
RAP1 truncation mutants led to elongated telomeres and
loss of telomere heterogeneity [54,63]. TRF2 has also
recently been shown to associate with the origin replication
protein ORC1 [64], which implicates the origin recognition
complex (ORC) in facilitating telomere replication. Despite
the critical role of the ORC complex in eukaryotic DNA
replication, how it is recruited to origins of replication is
poorly understood. Sequence-specific DNA-binding
proteins or epigenetic factors may play a role. In this case,
the specific interaction between TRF2 and subunits of the
ORC complex point to a possible mechanism for targeting
the ORC complex to the telomeres. However, whether TRF2
does have a role in telomere replication remains to be
determined.
Recent studies suggest that the TRFH domains are the first
modular domains identified in telomere proteins that can
recognize linear peptide sequences [13]. And those findings
have further solidified TRF1 and TRF2 as the major hubs
within the telomere interactome. The TRFH domains of
TRF1 and TRF2 display distinct specificities and affinities
for their targets, suggesting a new avenue of research for
probing the function of TRF1 and TRF2, and deciphering
how players from diverse pathways are recruited to the
telomeres.
P PO OT T1 1 a an nd d T TP PP P1 1 a an nd d t th he ei ir r f fu un nc ct ti io on ns s
While the telosome forms a platform to which additional
players can be recruited (Figure 1), complicated interactions
are also at play within the protein complex itself [11]. TIN2
and TPP1 are critical to its assembly [65], and the ssDNA-
binding protein POT1 serves as the effector of the complex in
its role of maintaining telomere integrity. Both POT1 and
TPP1 contain one or more oligonucleotide/oligosaccharide-
binding folds (OB folds) [66-70]. Recent work has
highlighted the evolutionary conservation in both structure
and function among OB-fold-containing proteins
participating in telomere maintenance and integrity, such as
POT1 and TPP1, compared with those involved in DNA
protection, such as the heterotrimeric replication protein A
(RPA) complex [66,67,71-77].
Genetic studies in yeast, Tetrahymena, plants, humans and
mice support an essential role for POT1 in maintaining
telomere integrity [7,78-82]. Unlike humans, mice contain
two isoforms of POT1 - POT1a and POT1b [79,80]. Recent
work has shown the functional dichotomy of these two
isoforms, and provided much-needed insight into the evo-
lutionary divergence and conservation of POT1 homologs in
different species [78-80,83]. Conditional knockout studies
of POT1a and POT1b suggest that both are needed for
complete protection and maintenance of the telomeres
[79,80,83]. While the two proteins have overlapping
functions and each may compensate to some extent for the
loss of the other, they are not interchangeable. In particular,
POT1a is essential for suppressing DNA damage responses at
telomere termini, whereas POT1b regulates the 3’ ssDNA
overhangs [79,80,83]. When the ends of chromosomes are
not coated and protected by proteins, the telomeres (with or
without the overhang) may be recognized as DNA damage,
eliciting DNA damage response pathways. POT1b appears
important for protecting the 3’ overhangs from degrading
nucleases. This functional difference may be achieved, in
part, through the interaction of POT1a and POT1b with
different sets of proteins in the telomere interactome. For
example, one potential target of POT1b could be nuclease(s)
that are involved in processing the 3’ overhang [79].
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Although both TRF2 and POT1 bind telomere DNA and are
required for telomere capping, recent studies indicate that
they regulate distinct signaling pathways [84,85]. Loss of
function of TRF2 in a number of mammalian cell types
(tumor and primary cell lines), and in cells from conditional
TRF2-knockout mice, elicits DNA damage responses
mediated mainly through the ATM pathway, whereas POT1
knockout triggers the DNA damage response pathway
initiated by the protein kinase ATR (ataxia telangiectasia
related) [84]. These results are consistent with the telomere
interactome map (Figure 1), where TRF2 interacts with the
MRN complex and DNA-PK, proteins that mediate repair of
double-strand breaks, with which ATM is preferentially
associated [53,54,56,86]. In addition, the repression of ATR
activity by POT1 is probably a result of POT1 binding
telomere ssDNA and inhibiting ATR activation by blocking
access of the single-strand binding protein RPA, by which
ATR is recruited, to the telomere [84,87]. As shown in the
interactome map, few proteins are known to bind directly to
POT1. How POT1 signals through pathways other than the
ATR pathway merits further investigation.
In the cilate Oxytricha nova, heterodimers of the OB-fold
telomere end-binding proteins TEBP-α and TEBP-β are
bound to the TTTTGGGG repeats of telomeric DNA. TEBP-
α contains three OB folds, two of which are involved in
ssDNA recognition while the third interacts with TEBP-β
[68]. Human POT1 is a homolog of ciliate TEBP-α.
Although TPP1 lacks an obvious OB fold, careful
biochemical, structural and molecular studies have revealed
that it does indeed contain an OB-fold structure, and that it
is a functional homolog of the ciliate TEBP-β [66,67].
Whereas TPP1 exhibits little or no telomere ssDNA-binding
activities in gel-shift experiments, a POT1-TPP1-DNA
ternary complex can form in these assays. TPP1 has also
been shown to enhance POT1 DNA-binding activity [66,67],
supporting the model that POT1 may interact with DNA in
the form of a heterodimer with TPP1. The TPP1-POT1
heterodimer has been postulated to modulate telomerase
access to the telomeres.
In ciliates, TEBP-β can also promote G-quadruplex forma-
tion [88]. G-quadruplexes are tetrads of hydrogen-bonded
guanine bases that can form in G-rich DNA and RNA
sequences, and upon which higher-order structures can be
built. Folding of telomere DNA into G-quadruplexes appears
to inhibit telomerase access. This activity is unlikely to be
conserved in TPP1, as TPP1 lacks the basic domain of TEBP-
β that is responsible for G-quadruplex-stimulating activity.
In contrast, POT1 has been shown to inhibit G-quadruplex
structure [89], suggesting evolutionary divergence in
G-quadruplex control mechanisms. The core telomere
proteins TIN2, TRF1 and TRF2 are not found in ciliates.
These proteins seem to have evolved for telomere homeo-
stasis in vertebrates, and may provide additional mecha-
nisms for regulating telomere G-quadruplex formation.
Both TPP1 and POT1 are critical for regulating telomere
length, and POT1 is the only telomere protein identified so
far that binds to telomere ssDNA. TPP1 has been shown to
be able to interact with telomerase both in vitro and in cells
[66,67] and its putative OB fold is required for telomerase
recruitment. In addition to direct binding, the POT1-TPP1
complex appears to enhance the processivity of the
telomerase component TERT in vitro [67]. Consistent with
this finding, expressing a TPP1 mutant lacking the OB fold
resulted in modest telomere shortening in human cells
compared to parental cells or cells expressing full-length
TPP1 [66]. Because TPP1 on its own does not bind ssDNA,
this probably means that POT1 and TPP1 function together
to recruit telomerase to telomeric ssDNA through the TPP1
OB fold, in addition to protecting telomere ends and nega-
tively regulating telomerase access. Generally, telomeres
only become accessible to the telomerase during the S phase
of the cell cycle. This is achieved through multiple mecha-
nisms, including regulation of telomerase expression and
activity, sequestering of telomeres, and coating of telomeres
with telomere-binding proteins such as POT1, which
presumably serves to block telomerase access.
The realization that there are two classes of OB-fold-
containing proteins with distinct functions has in turn
helped to establish a unified model regarding the function of
OB-fold-containing proteins in telomere overhang binding
(Table 1) [66-70]. While much conservation exists between
the various OB-fold-containing complexes, differences such
as DNA-binding specificities, domain structures, and
interaction partners help to set these proteins apart. From
yeast to human, RPA-like or TEBP heteromultimeric
complexes may have evolved for the more specialized
function of ssDNA protection at the telomeres [66,67,71-77].
C Co om mp pa ar rt tm me en nt ta al li iz za at ti io on n o of f t te el lo om me er ri ic c p pr ro ot te ei in n c co om mp pl le ex xe es s
Structural, temporal and developmental variation greatly
impact on the assembly and disassembly of the various sub-
complexes that make up the dynamic telomere interactome.
While numerous studies have been carried out to elucidate
protein-protein interactions and telomere localizations of
multiple factors within the interactome (for example, TRF1,
TIN2 and TRF2), surprisingly little is known regarding the
subcellular localization and regulated targeting of core telo-
mere proteins.
Proteins of the telosome have been found in cellular locations
other than the telomeres. For example, TRF2 and RAP1 have
been shown to associate with the Epstein-Barr virus origin of
replication [90], and TRF2 can be recruited to intra-satellite
double-strand breaks when the damage level is high [91]. The
growth status of human cells may influence the localization of
TIN2 [92]. In growth-arrested epithelial cells, TIN2 was found
to migrate into non-telomeric domains that contained the
protein HP1, a marker of heterochromatin. It is possible that
different complexes may form under these different conditions.
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Recent studies have indicated for the first time the impor-
tance of nuclear export and spatial control of telomeric
proteins in telomere maintenance in mammalian cells, as
endogenous TIN2, TPP1 and POT1 have been found to
localize in both the cytoplasm and the nucleus [93]. In
addition, as determined by bimolecular fluorescence com-
plementation assays [93,94], different pairs of telomeric
proteins appear to interact with each other in different
cellular compartments. Whereas TIN2-TRF2 interaction
takes place exclusively in the nucleus (including at telo-
meres), TIN2-TPP1 and TPP1-POT1 interactions occur in
both the cytoplasm and nucleus. These results suggested
telomere protein subcomplex formation in the cytoplasm.
Interestingly, a nuclear export signal (NES) has been
identified on TPP1 that directly controls the amount of TPP1
and POT1 in the nucleus. This NES resides next to the POT1-
recruitment domain on TPP1, raising the possibility that
interaction and nuclear localization of the TPP1-POT1
complex may be linked.
Binding of TIN2 to TPP1 promotes nuclear localization of
TPP1 and POT1, by a mechanism yet to be determined [93].
The finding that TIN2 promotes nuclear retention of TPP1
and POT1 suggests that TIN2 plays a dual role in telosome
assembly. While acting as a molecular tether for telosome
subunits, TIN2 also ensures nuclear targeting and assembly
of the entire complex. It would be of great interest to
determine whether there exist other signaling pathways that
control the nuclear import and export of telomeric
complexes. Unexpectedly, disrupting TPP1 nuclear export
can result in telomeric DNA damage response and telomere
length disregulation [93]. This underlines the importance of
spatial control of telomeric complexes, such that too much
TPP1 in the nucleus may be detrimental to cells, and TPP1
nuclear export may regulate the concentration of TPP1-POT1
in the nucleus. These findings suggest that coordinated
interactions among TIN2, TPP1 and POT1 in the cytoplasm
could regulate the assembly and function of the telosome in
the nucleus.
A Ac ck kn no ow wl le ed dg ge em me en nt ts s
This work is supported by NIH grants CA84208 and GM69572 and the
Welch Foundation. DL is supported in part by the American Heart Asso-
ciation. ZS is a Leukemia and Lymphoma Society Scholar.
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http://genomebiology.com/2008/9/9/232Genome B Bi io ol lo og gy y 2008, Volume 9, Issue 9, Article 232 Xin et al. 232.5
Genome B Bi io ol lo og gy y 2008, 9 9: :232
T Ta ab bl le e 1 1
E Ev vo ol lu ut ti io on n o of f t te el lo om me er re e- -e en nd d- -b bi in nd di in ng g p pr ro ot te ei in ns s c co on nt ta ai in ni in ng g t th he e O OB B f fo ol ld d
Species OB-fold proteinsStructure
Budding yeast CDC13-Stn1-Ten1, Est3RPA-like
Fission yeastPOT1-TPP1TEBPα/β-like
CiliateTEBPα-TEBPβ
TEBPα/β heterodimer
Vertebrates (frogs to humans)POT1-TPP1 TEBPα/β-like