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Telomere

Telomere-related Ageing and Cancer. Telomere. 20090400 김소은 20090410 김 준. Contents. Telomere. Telomere 는 ch r omosome 의 끝부분에 있다 . Telomere 가 없는 chromosome 은 sticky 하다 . The Nobel Prize in Physiology or Medicine 2009. End Replication Problem. Linear DNA 는 복제 시 끝부분이 점점 짧아져야 한다 .

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Telomere

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  1. Telomere-related Ageing and Cancer Telomere 20090400 김소은 20090410 김 준

  2. Contents

  3. Telomere • Telomere는 chromosome의 끝부분에 있다. • Telomere가 없는 chromosome은 sticky하다. The Nobel Prize in Physiology or Medicine 2009

  4. End Replication Problem • Linear DNA는 복제 시 끝부분이 점점 짧아져야 한다. • 그러나 실제로는 길이가 거의 유지되며 genetic information의 손실이 없다. The Nobel Prize in Physiology or Medicine 2009

  5. Telomere Discovery The Nobel Prize in Physiology or Medicine 2009 • Elizabeth Blackburn은 Tetrahynema에서 minichromosome을 분리시켰다. • Minichromosome에는 20~70회 반복되는 CCCCAA sequence가 있었다.

  6. Function of Telomere • Artificial linear DNA를 yeast에 그냥 넣을 때는 모두 분해되었다. • 그러나 여기에 Tetrahymena의 telomere를 붙이자, 분해되지 않았다. The Nobel Prize in Physiology or Medicine 2009

  7. Telomerase Discovery • Telomere, nucleotides, Tetrahymena extract를 섞자 telomere가 길어졌다. • Telomere의 길이를 늘리는 enzyme이 존재할 것이다. The Nobel Prize in Physiology or Medicine 2009

  8. Telomerase The Nobel Prize in Physiology or Medicine 2009 • Telomerase는 telomere와 sequence의 RNA template를 지닌 reverse-transcriptase이다.

  9. Telomere Structure Blasco, 2005 • Telomere에는 telomere maintenance에 중요한 여러 protein이 binding하여 structure를 이룬다.

  10. Discussion The Nobel Prize in Physiology or Medicine 2009 “진화적으로” telomere와 telomerase는 어떻게 생겨났을까?

  11. Contents

  12. Aging Werner syndromes http://www.wernersyndrome.org/ Blasco, 2005 • Telomerase가 없는 somatic cell의 telomere는 나이에 따라 점차 짧아진다. • Premature syndrome은 short telomere의 phenotype을 보인다.

  13. Mitotic Clock Theory Fig. 2. Mitotic clock theory • Telomere가 짧아지는 것은 cell의 proliferation을 제한한다. • Telomere shortening은 senescence,cancer와 관련이 있다. Blackburn, 2000

  14. Fusion Du, 2004 • Telomere 길이가 아주 짧아지면 chromosome fusion이 일어난다. • Premature syndrome에서도 이를 확인할 수 있다.

  15. Cell Death Du, 2004 • Telomere가 짧아지면 세포가 죽게 된다.

  16. Telomere Length Herrmann et al., 2001 • 가장 짧은 telomere가 fusion을 일으키며, fusion은 다시 apoptosis를 일으킨다. • Telomerase는 가장 짧은 telomere에 대한 preference가 있다.

  17. Chromosome Fusion Herrmann et al., 2001 • Telomere가 없는 것은 chromosome fusion과 아주 높은 상관관계를 보인다.

  18. Contents

  19. Cancer Telomere dysfunction And Telomerase reintroduction Blasco, 2005 • Chromosome instability는 telomerase가 다시 작동할 수 있게 한다.

  20. Tumor González-Suárezet al., 2000 • 짧은 telomere와 telomerase 결핍은 tumor를 억제한다.

  21. Epigenetic Regulation Blasco, 2005 • Telomere의 epigenetic regulation은 telomerase의 access를 조절한다. • Regulation에이상이 생기면 telomere가 길어지고, 이는 cancer를 유발한다.

  22. Blasco, 2005

  23. Contents

  24. Telomere Measurement http://www.scientificamerican.com/article.cfm?id=my-what-long-telomeres-you-have

  25. Cancer Therapy Mutant-Template Telomerase RNA(MT-hTer) and Anti-telomerase short-interfering RNA caused p53-independent cell growth inhibition and apoptosis, in telomerase-positive precancerous or cancer cells but not in telomerase-negative cells. Co-expression of MT-hTer and siRNA synergistically killed cancer cells.

  26. smaller and less vascularized tumors in mice than wild-type human telomerase RNA controls. Li, 2004

  27. Delivery of siRNA targeting hTERT Xiaa, 2011 biodegradable polyethylenimine containing multiple disulfide bonds (SS-PEI) was successfully applied as a potent non-viral carrier for intracellular delivery of the hTERTsiRNA in vitro and in vivo.

  28. Drugs and Vaccines in Clinical Trial Oligonucleotides(target template region of telomerase) In phase 2 clinical trial Telomerase Inhibitor Drug, Imetelstat(GRN163L) http://www.geron.com/products/productinformation/cancerdrug.aspx Telomerase Cancer Vaccine, GRNVAC1 Peptide vaccine, GV1001 http://www.geron.com/products/productinformation/cancervaccine.aspx http://www.kael.co.kr/02_product/01_bio_01.asp

  29. Anti-ageing Pill drdavesbest.com TA-65 is a naturally occurring single molecule found in the ancient Chinese herb Astragalus. TA-65 is a telomerase activator, which turns on the hTERT gene.

  30. Mechanismof GRN163L Harley, 2008 GRN163L is telomerase active site inhibitor.

  31. Discussion González-Suárezet al., 2000 DePinho, 2000 Telomeraseactivity를 조절하는 의약품은 Cancer 발생에 어떤 영향을 미칠까?

  32. Discussion • Cell의 senescence와 우리가 흔히 생각하는 “aging”은 어떤 관계가 있을까? • Chromosome마다 telomere 길이가 왜 다른 걸까? • 세포의 telomerase activity를 어떻게 측정할까? • 다른 therapy방법은 어떤 것이 있을까?

  33. Reference • http://www.wernersyndrome.org/ • The Nobel Prize in Physiology or Medicine 2009 • Maria A. Blasco (2005), Telomeres and Human Disease: Ageing, Cancer and Beyond, Nature reviews genetics, voloume 6, August 2005, 611-622 • Xiaobing Du, Johnny Shen, NishanKugan, Emma E. Furth, David B. Lombard, Catherine Cheung, Sally Pak, GuangbinLuo, Robert J. Pignolo, Ronald A. DePinho, Leonard Guarente, and F. Brad Johnson (2004), Telomere Shortening Exposes Functions for the Mouse Werner and Bloom Syndrome Genes, Molecular and cellular Biology, October 2004, 24(19), 8437–8446 • Eva González-Suárez, Enrique Samper, Juana M. Flores & María A. Blasco (2000), Telomerase-deficient Mice with Short Telomeres are Resistant to Skin Tumorigenesis, Nature genetics, volume 26, September 2000, 114-117 • Ronald A. DePinho (2000), The Age of Cancer, NATURE, Volume 408, 9 November 2000, 248-254 • Wei Xiaa,PeijunWanga,ChaoLinb,ZhuoquanLib,XiaolongGaoa,GuoliangWanga,XiaohuZhaoa (2011), Bioreduciblepolyethylenimine-delivered siRNA targeting human telomerase reverse transcriptase inhibits HepG2 cell growth in vitro and in vivo,Journal of Controlled Release,doi:10.1016/j.jconrel.2011.10.011 • Shang Li, Jonathan E. Rosenberg 1, Annemarie A. Donjacour, Inna L. Botchkina, Yun Kit Hom, Gerald R. Cunha, and Elizabeth H. Blackburn(2004),Rapid Inhibition of Cancer Cell Growth Induced by Lentiviral Delivery and Expression of Mutant-Template Telomerase RNA and Anti-telomerase Short-Interfering RNA,CancerRes,July15 • Calvin B. Harley (2008), Telomerase and cancer therapeutics, NATURE REVIEWS|CANCER, Volume 8 , March2008, 167-179

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