CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 10, November 2012
564
AFRICA
Diabetic patients, more than any other subset, show the greatest
difference in telomere length compared to non-diabetics.
26
Type
2
diabetes is considered a cardiovascular risk equivalent.
27,28
It
is postulated that telomere shortening induces pancreatic
β
-
cell
senescence. Like atherosclerosis, diabetes is thought to be a
premature-ageing syndrome.
26
The study of telomeres may therefore provide in a single
marker, the combined influence of genetics, environmental
risk and ageing in predicting risk and identifying susceptible
individuals prone to developing coronary artery disease. This is
especially relevant in our community, which has a high incidence
of both premature coronary artery disease and type 2 diabetes.
29,30
Structure and function of the telomere
complex
Telomeres have a dynamic structure that is thought to switch
between a closed, protected state and an open, extendable
state, which allows the DNA terminus to undergo replication.
The protected state is necessary for safeguarding the integrity
of genomic material, whereas the extendable state allows the
enzyme telomerase to extend short telomeres (Figs 1, 2).
31
Telomere components include:
•
The DNA component: this consists of tandem repeats of the
hexanucleotide 5
′
-
TTAGGG-3
′
(
T
=
thymine, A
=
adenine,
G
=
guanine) and has a high guanine content. The bulk of
telomeric DNA is arranged in the double-stranded configu-
ration, which then ends in a single-stranded extension. The
single-stranded overhang folds back to form a terminal loop,
which prevents the end of the telomere from being recognised
as a damaged, broken end. Telomere shortening is thought to
destabilise this loop.
8,14,31
•
Shelterin proteins: these proteins bind and protect the loop
structure and are termed shelterin because they shelter the
chromosome end.
32
An inability to form the terminal loop
will leave the chromosome ends uncapped, resembling a DNA
break and provoking DNA repair mechanisms. The shelterin
complex consists of six proteins, which have specific func-
tions in telomere replication and end protection.
The six proteins are: TRF1 and TRF2: telomere repeat-
binding factors 1 and 2, which are the two major proteins;
POT1: protection of telomeres 1; TPP1: tripeptidyl peptidase
1;
TIN2: TRF1-interacting protein 2; and RAP1: repressor
activator protein 1. Whereas the shelterin proteins are a
constant fixture at the telomere end, other accessory proteins
are intermittently recruited to the telomere. These proteins
include the tankyrases tank 1 and 2, Ku 70/86 and poly-ADP
ribose polymerase-1 (PARP-1), which influence the control of
telomere length and repress the DNA damage response.
31,33,34
•
The CST complex: an additional telomere-associated
complex, known as the CST, has recently been identified. It
binds single-stranded DNA and appears important for both
telomere protection and replication.
31
•
Telomerase: in order for cellular repair to take place as well
as for species survival, stem cells and reproductive cells
need to be able to proliferate without the penalty of progres-
sive telomere shortening.
31
These cells, unlike somatic cells,
contain the enzyme telomerase, which is capable of adding
DNA sequences to the chromosome terminus to compensate
for the loss sustained during replication. Telomerase is made
of Terc – the RNA component that serves as a template for
the synthesis of new telomeric DNA, and TERT – a reverse
transcriptase which is the catalytic subunit representing the
rate-limiting step in telomerase activity.
12,14,33,35
A variety of
accessory proteins have important roles in telomerase biogen-
esis and localisation.
Telomere homeostasis
Telomere length in proliferating cells is influenced by the
following factors.
•
Factors that shorten telomeres:
––
telomere attrition during cell division
––
DNA damage due to oxidative stress caused by environ-
mental risk factors
––
specific exonucleases involved in the degradation of RNA
primers used for DNA replication
––
deficiency of Rad 54, which is involved in DNA repair
––
histones: methylation of histones H3 and H4 diminishes
telomerase activity.
36
Fig. 1. A simplified scheme depicting the structure of the
telomere and its location on the chromosome in the cell.
Reproduced with permission.
126
Fig. 2. Scheme showing the terminal end of the telomere
concealing the terminal single-stranded part with the
help of the shelterin complex. Reproduced with permis-
sion.
126
nucleus
chromo-
some
telomere
double-
stranded
DNA
single-stranded DNA
telomere
shelterin complex
T-loop
TRF2
TRF1
TPP1POT1
RAP1
TIN2
