TELOMEREPOOJA S NATHANS4 BT 25

The functional units: Genes

▪ Genetic information, or "genes,” are a series of bases called adenine (A), guanine (G), cytosine (C), and thymine (T).

▪ These base pairs make up the sequences, or instructions needed to form proteins, our cellular machinery.

What is a human telomere?

▪ Telomeres are repetitive nucleotide sequences located at the terminal of linear chromosomes of most eukaryotic organisms.

▪ Its name is derived from the Greek nouns telos ='end' and merοs = 'part’.

▪ Most prokaryotes do not have telomeres. ▪ When they are completely worn away, the cell is destroyed.▪ Telomerase provides the necessary enzymatic activity to restore and

maintain the telomere length.▪ Telomeres consist of variable numbers of a repetitive sequence,

(TTAGGG)n. This sequence of TTAGGG is repeated approximately 2,500 times in humans.

▪ Telomeres are stabilised by the aptly named protein complex, shelterin (de Lange, 2005).

▪ In humans there are 46 chromosomes and thus 92 telomeres (one at each end) in a single cell.

Discovery

Function of Telomere

▪ They protect the chromosomes.▪ They separate one chromosome from another in

the DNA sequence▪ Without telomeres, the ends of the chromosomes

would be "repaired", leading to chromosome fusion and massive genomic instability.

▪ Telomeres are also thought to be the "clock" that regulates how many times an individual cell can divide. Telomeric sequences shorten each time the DNA replicates.

Think of it like this….

▪ Telomeres effectively "cap" the end of a chromosome in a manner similar to the way the plastic on the ends of our shoelaces "caps" and protects the shoelaces from unraveling. (Geron corporation)

Telomeres & AgingHealthy human cells are mortal because they can divide only a finite number of times, growing older each time they divide. Thus cells in an elderly person are much older than cells in an infant.

Why do telomeres get shorter each time a cell divides?▪ Before a cell can divide, the chromosomes within it are

duplicated so that each of the two new cells contains identical genetic material. Two strands of DNA must unwind and separate.

▪ While replicating DNA, the eukaryotic DNA replicating enzymes, cannot replicate the sequences present at the end of chromosomes. Hence these sequences and the information they carry may get lost.

▪ They cap the end sequences and themselves get lost in the process of DNA replication.

▪ In 1972, James Watson called this as End-replication problem.

End-replication problem

Dna replication

• DNA replication does not begin at either end of the DNA strand, but starts in the center DNA polymerases move in the 5' to 3' direction, there is a leading and a lagging strand on the DNA molecule being replicated.• On the leading strand, DNA polymerase can make a complementary DNA strand without any difficulty because it goes from 5' to 3'.

• However, there is a problem going in the other direction on the lagging strand. To counter this, short sequences of RNA acting as primers attach to the lagging strand a short distance ahead of where the initiation site was. • The DNA polymerase can start replication at

that point and go to the end of the initiation site. This causes the formation of Okazaki fragments.• More RNA primers attach further on the DNA

strand and DNA polymerase comes along and continues to make a new DNA strand.

• Eventually, the last RNA primer attaches, and DNA polymerase, RNA nuclease, and DNA ligase come along to convert the RNA (of the primers) to DNA and to seal the gaps in between the Okazaki fragments.

• But, in order to change RNA to DNA, there must be another DNA strand in front of the RNA primer. This happens at all the sites of the lagging strand, but it does not happen at the end where the last RNA primer is attached.

• Ultimately, that RNA is destroyed by enzymes that degrade any RNA left on the DNA. Thus, a section of the telomere is lost during each cycle of replication at the 5' end of the lagging strand's daughter.• Thus, a section of the telomere is lost

during each cycle of replication at the 5' end of the lagging strand's daughter.

SOLUTION TO END REPLICATION PROBLEM

TELOMERASE▪ Telomerase enzyme adds bases to the ends of telomeres. ▪ Specialized reverse transcriptase.▪ In young cells, telomerase keeps telomeres from wearing down too much. But as cells divide repeatedly, there is not enough telomerase, so the telomeres grow shorter and the cells age.

• Telomerase is turned off in somatic cells • But remains active in sperm and eggs,

which are passed from one generation to the next.

• If reproductive cells did not have telomerase to maintain the length of their telomeres, any organism with such cells soon would go extinct.

• Telomerase activity is low or absent in normal cells, when compared to cancer cell.

What role do telomeres play in cancer?• Telomeres were first discovered in cancer

cells because, cancer cells are saturated with an enzyme called telomerase.• Telomerase is the key enzyme for human

cells to acquire immortality.• As a cell begins to cancerous, it divides

more often and its telomere becomes very short. If its telomeres get too short, the cell may die.

• The normal cell is devoid of telomerase activity.• It can escape this fate by becoming

cancerous cell by activating telomerase (or) ALT pathway is activated, resulting in abnormal telomere lengthening & proliferative growth.• Telomerase is over expressed in

many cancers cells.

factors that may influence telomere length

Diseases Affected By telomere Shortening

CardiovascularCancerCOPDDegenerative Disc DiseaseAlzheimer’sOsteoarthritisRheumatoid Arthritis OsteoporosisGeneral ImmunitySkin AgingMacular DegenerationLiver Cirrhosis

Muscular DystrophyCell & Tissue Transplants AIDSProgeriaDyskeratosis CongenitaIdiopathic Pulmonary FibrosisCri du Chat syndrome Down’s SyndromeFanconi’s AnemiaTuberous SclerosisWerner’s SyndromeAnd, Aging Itself???????

•Right Exercise•Anti-Oxidants•Omega 3’s•Vitamin D3•Don’t Smoke

• Weight Management

• Reduce Stress• Reduce Depression• Reduce Pessimism• Be Happy!

Keeping Telomeres Long

Unlocking the telomere is the MOST important event in the history of anti-aging medicine

THANK YOU