Medical Genetics - V. M. Zaporozhan 2005

Introduction to Medical Genetics
Cytological Foundations of Heredity
Structure and Functions of the Nucleus and Chromosomes — Telomeres and Telomerase

Telomeres. The terminal regions of Chromosomes are called telomeres. They consist of specific sequences of six nucleotide pairs (TTAGGG/AATCCC) repeated several thousand times. The length of a chromosome's telomeric end in human embryonic Cells is 10-15 kb.

Diagram of The Structure of telomeric ends:

Class="center">(5')TTAGGG-...-TTAGGG- -AATCCC-.. -AATCCC(3')

(3')AATCCC-...- AATCCC- -TTAGGG-..-TTAGGG5')

Telomeric repeats do not carry Genetic information. They are associated with specialized telomeric Proteins and attached to the nuclear matrix.

The enzyme DNA polymerase is unable to ensure the reduplication of the terminal regions of a chromosome.

Reduplication of the terminal regions of telomeres is possible in the presence of a specialized enzyme called telomerase. This enzyme contains an RNA region complementary to a single repeat of telomeric DNA. Terminal repeats of the telomere are synthesized from this telomerase RNA region according to THE PRINCIPLE OF complementarity.

Telomerase maintains high activity in Embryonic Stem Cells. In somatic cells, telomerase is absent or its activity is significantly reduced. In the absence of telomerase, the telomeric end is incompletely reduplicated. With each Cell Division, the telomere shortens by 50-65 bp. The loss of a portion of telomere repeats does not affect genome functioning, as telomeres do not carry genetic information. This constitutes the primary role of telomeres: by their very existence, they protect more vital DNA regions from damage. However, There is a specific lower limit to which a telomere can shorten. When telomere length approaches a critical level, cells begin to age, and once this level is reached, they die. Telomere shortening is one of the possible mechanisms triggering programmed cell death. Telomeres determine the number of cell divisions that cells can undergo after losing telomerase activity.

Other Functions of telomeres include the following:

a) they ensure the structural integrity of chromosomes and prevent chromosomes from fusing with one another;

b) they anchor chromosomes to the nuclear matrix, which is essential for the proper orientation of chromosomes within The Nucleus;

c) they ensure the proper pairing (synapsis) of chromosomes during Meiosis;

d) they protect the terminal regions of DNA from degradation by Enzymes known as exonucleases (which are capable of cleaving NUCLEOTIDES from the ends of DNA molecules);

e) they influence Gene Expression (it has been established that the expression of genes located adjacent to telomeres is reduced; significant telomere shortening can activate subtelomeric genes).

Medical significance of telomeres and telomerase. This issue is viewed from at least two Perspectives.

First, telomere shortening is one of the causes of premature Aging syndromes (progerias). An example is Hutchinson-Gilford syndrome, or childhood progeria. Affected individuals exhibit symptoms of aging at an early age (senile Changes in the Skin, musculoskeletal, cardiovascular, and other systems), and growth is stunted. Among reported cases, patient life expectancy ranged from 7 to 27 years, with an average age of death of 12 years. Patients exhibit congenitally shortened telomeres.

Second, malignant growth is associated with telomeres. Malignant tumor cells are capable of dividing indefinitely under certain conditions, meaning they become immortal. Cell immortality is only possible if telomerase is reactivated within them or if alternative mechanisms of telomere reduplication emerge. Telomerase is considered a biochemical marker of human malignant tumors. Telomerase activity correlates with the degree of tumor malignancy.