Chemistry Reference
In-Depth Information
TPP1
TIN2
hRAP1
PARP2
ERCC1/
XPC
TRF2
MRE 11
Rad 50
Nbs1
WRN
ATM kinase
Ku
TPP1
POT1
TIN2
POT1
POT1
TPP1
TPP1
TIN2
TIN2
hRAP1
PARP2
WRN
BLM
PINX1
ERCC1/
XPC
TANK1
et2
TRF1
TRF2
MRE 11
Rad 50
Nbs1
ATM kinase
Ku
ATM kinase
Ku
Figure 7.2
The shelterin complex and associated proteins. T-loop formation has been pro-
posed as a structure capping the end of telomeres. It consists of the invasion of the 3
G-
overhang into the duplex telomeric DNA. Associated telomeric proteins are involved in this
complex: TRF1, TRF2 and POT1 bind directly to telomeric DNA, whereas TPP1, TIN2 and
RAP1 interact with them. Other proteins that are not specifi c for telomeres have also been
associated with this complex. They include Apollo, which appears to protect chromosome
ends from being processed as DNA damage, and DNA damage proteins: PINX1, Ku 70/80,
TANK1/2, ATM-kinase, PARP2, ERCC1/XPC, MRE11, Rad 50, Rbs1
′
telomeric DNA: TRF1 and TRF2 bind to the double-stranded structure through
their Myb-type DNA binding domain
19 - 21
and POT1 binds to the G-rich 3
overhang
through two oligonucleotide/oligosaccharide binding domains.
22
The three other
proteins allow the connection between the double-stranded telomeric DNA and its
3
′
extremity: TIN2 binds to TRF1 and TRF2; TPP1 binds to TIN2 and POT1; Rap1
binds to TRF2.
23
Two telomeric proteins, TRF2 and POT1 are directly involved in
the maintenance of the structure of telomeres.
24
In particular, as shown by an elec-
tron microscopy study, TRF2 is thought to promote the formation of the t-loop,
which consists of an invasion of the G-rich overhang in the double-stranded telom-
eric DNA,
25
and is supposed to protect the chromosome extremity from degrada-
tion
26
(Figure 7.2 ). Moreover, it has been found that expression of a dominant - negative
mutant allele of TRF2 induces: (i) recognition of telomeres as DSB, (ii) activation
of the ATM/p53 DNA damage response pathway, (iii) end-to-end fusions of chro-
mosomes and (iv) accelerated senescence entry.
27 - 29
TRF2 is overexpressed in some
cancer cell lines,
30 - 32
and it has been shown that the inhibition of TRF2 can reduce
tumourigenicity of melanoma cancer cell lines.
33
This suggests that TRF2 is strongly
involved in telomere capping in cancer cells and could be a good target for antican-
cer therapy. POT1 has been shown to act either as an activator or as a repressor of
the enzyme responsible of telomere elongation, telomerase (see below), via its
interaction with TRF1 and TPP1.
34 - 38
Dysfunctional or uncapped telomeres, created
through destabilization of the shelterin by TRF2 or POT1 inhibition, leads to the
DNA damage response,
3,35,39 - 42
loss of the 3
′
- G - overhang and aberrant homologous
recombination.
43,44
In conclusion, the protective function of telomeres depends
essentially on the stability and integrity of the shelterin, which could be perturbed
by modifi cation of the amount of telomeric proteins bound to DNA.
′
