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Telomere and telomerase


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Telomere and telomerase

  2. 2. Martinez, P., and Blasco, M., 2011. Telomeric and extra-telomeric rolesfor telomere-binding proteins. Nature Reviews Cancer. (3) 161-176 2
  3. 3.  INTRODUCTION Telomeres• The ends of chromosomes.• Functions: o Protect chromosome from degradation. o Regulate telomerase activity at chromosome ends. o Essential for chromosome stability 3
  4. 4. • Structure o Formed by tandem repeats of TTAGGG sequence. o Bounded by a specialized six- proteins complex known as shelterin. o Elongated by telomerase 4
  5. 5.  subunits of shelterin TRF1-interacting protein 2 Organizing protein Protection of telomeres protein 1Repressor-activator protein 1 Telomeric repeat binding factors 1&2 (Transcriptional regulation) • Telomeric roles of shelterin:  Protection and recombination (TRF1, TRF2, TIN2, TPP1, and RAP1)  Length regulation (TRF1, TRF2, TIN2, TPP1 and RAP1).  Inhibition DDR (POT1, RAP1, TRF1, and TRF2). 5  Telomere replication (TRF1)
  6. 6.  Telomerase • Structure Is a two partner enzyme, the reverse transcriptase catalytic subunit (TERT) and the RNA component (TERC), which recognizes the hydroxyl group at the 3’ end of G-strand overhang and elongates the telomere • Function o Telomere dysfunction causes ageing or cancer depending on the DNA damage response. 6
  7. 7.  OBJECTIVE The present paper discusses the role of telomeric proteins in cancer and ageing through modulating telomere length and protection. And regulating gene expression by binding to non-telomeric sites. 7
  8. 8.  DISCUSSION  Factors that influence telomere function • Telomerase • The telomeric chromatin • The shelterin complex 8
  9. 9. • Telomerase o During each cell division cycle, telomeres shorten as a result of the incomplete replication of linear DNA molecules by conventional DNA polymerase. o Telomerase compensates for telomere attrition through addition of TTAGGG repeats by TERT onto the chromosome ends by using an associated RNA component as a template TERC 9
  10. 10. o But this is not sufficient mechanism to maintain the telomere length.o Indeed, there are some conditions may lead to accelerate the rate of telomere shortening such as:  age in most tissues.  Some cases of aplastic anaemia and idiopathic pulmonary fibrosis are linked to germline mutations in TERC and TERT  some diseases are characterized by the premature loss of tissue renewal and premature death (dyskeratosis congenita) 10
  11. 11. • The telomeric chromatin 11
  12. 12. o TERRA:Telomere repeat containing RNAso TelRNA: telomeric RNAs. 12
  13. 13. • The shelterin complex RAP1 is dispensable for telomere capping but prevents telomere recombination and fragility. Thus, RAP1 is not a telomere protective protein, in contrast to the rest of proteins. So the role of RAP1 is telomerase regulation 13
  14. 14.  Extra-telomeric roles for a telomeric protein 14
  15. 15.  Telomere dysfunction and genomic instability • Genomic instability is a prominent characteristic of most cancer types that has an essential role in tumorigenesis by accelerating the accumulation of genetic changes that are responsible for cancer cell evolution. 15
  16. 16. • One of the important source of genomic instability is telomere shortening.• Telomere dysfunction can causes by deficient of telomerase and/or the shelterin proteins, either owing to the loss of telomeric repeats or owing to the loss of the telomere protective structure, causes genome instability and thereby affects tumorigenesis.• The molecular mechanisms that related to telomere defects are: o Breakage-fusion-bridge cycles. o Defects in telomeric DNA replication. o The susceptibility of telomeric DNA to genotoxic damage. o Cell cycle control and endoreduplication. 16
  17. 17. o Breakage-fusion-bridge cycles 17
  18. 18. o Defects in telomeric DNA replication 18
  19. 19. o The susceptibility of telomeric DNA to genotoxic damage T A T A UV G C G C G C Replication G C T A T A G C G C G C G C 19
  20. 20. o Cell cycle control and endoreduplication  Limiting genome replication to once per cell cycle is essential for maintaining genomic stability.  Cancer cells are usually aneuploid, with highly variable chromosome numbers, ranging from hypodiploidy and hypertetraploidy. 20
  21. 21.  Telomere shortining and telomere dysfunction have been shown to trigger polyploidization.example Mitosis Tetraploid 21
  22. 22.  Telomerase and anticancer treatment o The link between the inability to maintain telomeres with age and consequent declining health, including the increased risk of degenerative diseases and cancer, has suggested that telomerase is appealing target for the treatment of these diseases. 22
  23. 23. o Several factors make telomerase inhibition as an anticancer treatment a safe and rather specific therapy:  Telomerase is expressed in 85% of tumours from all types of cancers and so it would be widely applicable.  The likelihood of developing resistance mechanisms is low.  The different telomerase expression levels in healthy cells versus tumour cells, suggest a high degree of tumour specifity and a low risk of toxicity to normal tissues. 23
  24. 24. o Telomerase inhibitor  Drugs; inhibit telomerase enzymatic activity.  Active immunotherapy.  Gene therapy.  Agent that block telomerase biogenesis 24
  25. 25.  Conclusion Telomeres are still fertile field, and it needs to identify new interactingfactors between telomerase and shelterin components, and to understand theirbiological function and how their activities are controlled in more detail.“Such knowledge would not only enhance our appreciation of the molecularmechanisms underlying telomere maintenance but would also provide valuableinsights into human genetic disease, ageing and cancer, and thereby provideopportunities for the better management of human health and disease”. 25
  26. 26. Q&AThank you 26