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REVIEW

SA JOURNAL OF DIABETES & VASCULAR DISEASE

54

VOLUME 12 NUMBER 2 • NOVEMBER 2015

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 configuration, 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 functions

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 progressive

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 biogenesis 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 environmental

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

• Factors that maintain telomere length:

– Telomerase: in addition to the level of telomerase within a

cell, telomere length is also dependent on the delivery of

Figure 1

. A simplified scheme depicting the structure of the telomere and its

location on the chromosome in the cell. Reproduced with permission.

126

Figure 2

. Scheme showing the terminal end of the telomere concealing the

terminal single-stranded part with the help of the shelterin complex. Reproduced

with permission.

126