A CONCEPTUAL APPROACH TO TELOMERE SHORTENING TELOMERASE ACTIVITY

A CONCEPTUAL APPROACH TO TELOMERE SHORTENING & TELOMERASE ACTIVITY January 2015 – Vahid R. Abbasi 1

Life + Genetic Degradation At The Ends of Chromosomes 2

Paper References A Review Article by Rune Toftgard, Member of the Nobel Assembly ( http: //nobelprize. org) about the research that was awarded by 2009 Nobel prize in Medicine & Physiology: 3

Textbook References Genetics, A Conceptual Approach By Benjamin A. Pierce, The 4 th edition © 2012 ISBN-13: 978 -1 -4292 -3250 -0 ISBN-10: 1 -4292 -3250 -1 Concepts of Genetics By William S. Klug, The 10 th edition © 2012 ISBN-13: 978 -0 -321 -72412 -0 (student ed. ) ISBN-10: 0 -321 -72412 -7 (student ed. ) 4

Textbook Reffrences 5

What We Discuss: 1 - Title & References 2 - Introduction 3 - Telomere Structure & Functions 4 - Telomere Throughout the Evolution 5 - A Quick glance to Linear DNA Replication 6 - End Replication Problem 7 - Telomerase Structure 8 - Telomerase Bio-Activity 9 - Conclusions 10 - Telomerase, the Key to Immortality? ! 6

We Live in the Age of Genetics & Genomics Since 1962 , 22 Nobel prizes have been awarded to the researches of Genetics & Genomics and the last one was devoted in 2009 Nobel prize in Medicine & Physiology was awarded for the discovery of how chromosomes are protected by Telomeres and the enzyme Telomerase (Elizabeth H blackburn , Carol W. Greider & Jack W. Szostak) 7

Telomere Structure - Telomeres are the natural ends of a chromosome - Pioneering work by Hermann Muller (on fruit flies) and Barbara Mc. Clintock (on corn) showed that chromosome breaks produce unstable ends that have a tendency to stick together and enable the chromosome to be degraded. - Because attachment and degradation do not happen to the ends of a chromosome that has telomeres, each telomere must serve as a cap that stabilizes the chromosome, much as the plastic tips on the ends of a shoelace prevent the lace from unraveling. 8

Telomere Structure – 3’ G-Rich Overhang First discovered by Elizabeth Blackburn and Joe Gall in their study of Micronuclei in the ciliated protozoan Tetrahymena—the DNA at the protozoan’s chromosome ends consists of the short tandem repeating sequence TTGGGG (G-Rich Strand). In a similar way, all vertebrates contain the sequence TTAGGG This is 12 -16 Nucleotides long in Tetrahymena and several hundred. But How this tandemly repeated DNA confers inertness to the chromosome ends? ! 9

Telomere Structure / T-Loop 10

Telomere Structure -Shelterin Complex 11

Telomere Sequence Preservation Through Evolution is Striking! Telomeric DNA sequences have been highly conserved throughout evolution, reflecting the critical function of telomeres. 12

Normal DNA Replication 13

End Replication Problem 14

No End Replication Problem/ Circular Prokaryotic DNA 15

Telomere Shortening 1 - Each time a cell divides, an average person loses 30 to 200 base pairs from the ends of that cell's telomeres 2 - Cells normally can divide only about 50 to 70 times, with telomeres getting progressively shorter until the cells become senescent, die or sustain genetic damage that can cause cancer. Example: In human blood cells, the length of telomeres ranges from 8, 000 base pairs at birth to 3, 000 base pairs as people age and as low as 1, 500 in elderly people 16

The Telomerase Enzyme - Telomerase is a unique ribonucleoprotein complex whose principal role is the maintenance of telomeres, the heterochromatic structures made of G-rich repeated sequences - Human telomerase is composed of two main subunits: the human telomerase RNA (TR), which harbors an 11 nucleotide long sequence (in human) acting as a template for synthesis of telomeric repeats, and the telomerase reverse transcriptase (TERT), which is the core catalytic subunit of the enzyme. 17

The Telomerase Bio-activity 18

The Telomerase Bio-activity 19

Conclusions of the Discovery Stage 1 – Blackburn, Greider and Szostak solved a longstanding fundamental problem in biology; how can the ends of chromosomes be maintained and spared from erosion or rearrangement during repeated cellular divisions? They opened a whole new research field related to the all Life science 2 - By ingenious genetic experiments they demonstrated that chromosomal termini have an evolutionarily conserved structure and function. 3 - They have discovered how the conserved function of chromosomal telomere repeat sequences protects against degradation and recombination events and have identified a new enzyme complex, telomerase. 4 - Deficiency of telomerase results in a so called replicative senescence. 20

Conclusions of the Discovery Stage 5 - most cancer cells maintain telomeres via increased telomerase activity. 6 - These Studies have provided very important insights into other areas of high medical relevance such as: ageing and hereditary disease syndromes although the connections are more complex than initially anticipated. 7 - The discoveries have also led to the development of new therapeutic strategies for cancer treatment based on the targeting of telomerase activity or expression that are now undergoing clinical testing. (such as GRN 163 L drug that has had successful clinical trials) 21

Telomerase, The Key to Immortality ? Thank you for your attention 22

Textbook References Genetics, A Conceptual Approach By Benjamin A. Pierce, The 4 th edition © 2012 ISBN-13: 978 -1 -4292 -3250 -0 ISBN-10: 1 -4292 -3250 -1 Concepts of Genetics By William S. Klug, The 10 th edition © 2012 ISBN-13: 978 -0 -321 -72412 -0 (student ed. ) ISBN-10: 0 -321 -72412 -7 (student ed. ) 23

Textbook Reffrences 24

Paper References A Review Article by Rune Toftgard, Member of the Nobel Assembly ( http: //nobelprize. org) about the research that was awarded by 2009 Nobel prize in Medicine & Physiology: 25