Chemistry Reference
In-Depth Information
7.3 Telomerase
Cells escape limits of proliferation by maintaining a constant length of their telom-
eres. This is mainly due to telomerase, a telomere-specifi c reverse transcriptase that
was fi rst identifi ed in 1985.
45
Telomerase is activated and expressed in 85% of cancer
cells, in germ cells, some stem cells
46,47
and at a very low rate in some epithelial and
intestinal cells.
48
It functions by adding telomeric repeats GGTTAG at the end of
the 3
-G-overhang of telomeres, using an RNA template complementary to the telo-
meric sequence.
49
This mechanism prevents replicative senescence, thus conferring
on cells unlimited proliferation.
50
Indeed, it has been shown that when telomerase
was introduced into normal cells, it resulted in an extension of their life span.
51
Therefore, telomerase has been proposed as one of the hallmarks of cancer cells
52
and as a cancer marker or prognosis factor.
53
Telomerase consists of two main components: a protein component reverse
transcriptase, hTERT, (127 kD) that contains conserved catalytic reverse tran-
scriptase motifs,
54
and a large RNA of 451 nucleotides, hTR, (153kD). It contains a
template complementary to telomeric sequences, and other critical conserved
regions essential for the assemblage of hTERT with hTR or for telomerase activ-
ity
55,56
(Figure 7.3). Recently, a third partner, dyskerin, a pseudouridine synthase
belonging to the H/ACA box ribonucleoproteins, has been identifi ed as an essential
component of the telomerase complex
57,58
that probably binds to the H/ACA motif
of hTR. Moreover the telomerase trimeric complex has been proposed to be associ-
ated in cells with about 30 other regulatory proteins involved in biogenesis, traffi ck-
ing and recruitment to telomeres.
57,59
′
hTR
hTR
CAAUCCCAAUC
TTAGGGTTAGG
CR4-5
hTERT
Pseudoknot
(CR2-3)
3'
H/ACA
(CR6-8)
5'
template
CR7
Figure 7.3
Telomerase is composed of two main components: a protein component that
contains the catalytic reverse transcriptase motif (hTERT) and a large RNA of 451 nucleotides
(hTR) containing the template region able to elongate the 3
extremity of telomeres. Other
proteins, that are not necessary for the
in vitro
telomerase activity, have been associated with
telomerase
in vivo
, such as dyskerin. In addition to the template, many structural domains of
hTR are conserved among the species (in grey boxes). They are involved in the assemblage
of hTR with hTERT, in telomerase activity or in hTR processing
′
