Telomerase: Cancer and the Philosopher’s Stone

Telomerase:Cancer and the Philosopher’s Stone Sapana Vora 1 March 2007 Biology 445

Table of Contents • Chapter 1: Telomeres • Chapter 2: Telomerase: Function • Chapter 3: Telomerase: Structure • Chapter 4: Telomerase and Cancer • Epilogue • Bibliography

telomere telomere Ch.1- Telomeres: Getting the Short End • Specialized nucleoprotein structures at chromosome ends • Repetitive arrays of guanine-rich hexameric DNA and telomere-binding proteins • Protect chromosomes from damage and degradation Human telomeric repeat sequence: 5’- TTAGGG -3’ Page 1

Site of next primer Lagging strand 5’ 3’ 3’ 5’ 5’ 3’ DNA Polymerase Leading strand DNA Replication Anyone? RNA primer for Okazaki fragment Page 2

Telomeres during DNA Replication • Lagging strand Okazaki fragments leave unfinished 5’ ends • No complementary strand DNA degrades Page 3 Image: http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T/Telomeres.html

Chromosomal Alzheimer’s in Action Round 1 5’ 3’ 3’ 5’ 5’ 5’ 5’ Round 30 3’ 3’ 3’ 3’ 3’ 3’ 5’ 5’ 5’ Round 60 Round 90 Page 4

How Do Cells Keep from Dying? • If all cells lost telomeric DNA and thus suffered irreparable DNA damage, immortal cell lines could not exist. • But they do exist: • germline cells (including ES cells), • adult stem cells, • cancer cells Page 5

Ch.2- Tying Up Loose Ends • Telomerase: • Telomerase is a reverse transcriptase that specifically synthesizes telomeric DNA • Is a type of DNA polymerase • Promotes stability of chromosomes • Protects linear DNA from degradation at chromosome ends • Is repressed in most cell types Page 6

Ch.3: Of Subunits and Structure • Ribonucleoprotein (made of RNA and protein): • RNA- snoRNA-like (small nucleolar RNA) molecule called TERC (telomere RNA component) • Protein- TERT (telomere reverse transcriptase) provides catalytic action Page 7

Structure and Action Page 8

Ch.4- Telomerase’s Role in Cancer Page 9

Telomerase Activity in Cancer Immunohistochemical localization of hTERT protein in normal and cancer cells Page 10 Shay, J. W. et al. Hum. Mol. Genet. 2001 10:677-685; doi:10.1093/hmg/10.7.677

Telomerase: The Philosopher’s Stone M1 = replicative senescence (arrested proliferation with continued metabolism M2/crisis = very short telomeres and widespread apoptosis Page 11

We’ve Seen This Before… Round 1 5’ 3’ 3’ 5’ 5’ 5’ 5’ Round 30 3’ 3’ 3’ 3’ 3’ 3’ 5’ 5’ 5’ Round 60 Round 90 Page 12

Round 1 5’ 3’ 3’ 5’ 5’ 5’ 5’ Round 90 Round 60 Round 30 3’ 3’ 3’ 3’ 3’ 3’ 5’ 5’ 5’ Cancer Cells Do It Differently Page 13

Epilogue: Cancer Therapeutics? • Telomerase is expressed almost exclusively in malignant cells… • But… • Telomere length varies in different cancer cells • ALT (alternate lengthening of telomeres) mechanisms Page 14

Bibliography 1. Chen, et al. “Secondary Structure of Vertebrate Telomerase RNA.” Cell, 2000. Vol. 100 (5): 503-514 2. Counter, et al. “Telomerase activity is restored in human cells by ectopic expression of hTERT (hEST2), the catalytic subunit of telomerase.” Oncogene, 1998. 16: 1217-1222 3. Granger, et al. “Telomerase in cancer and aging.” Critical Reviews in Oncology/Hematology, 2002. 41 (1): 29-49 4. Hahn. “Role of Telomeres and Telomerase in the Pathogenesis of Human Cancer.” Journal of Clinical Oncology, 2003. Vol. 21 (10): 2034-2043. 5. Kimball’s Biology Pages. John W. Kimball. 23 September 2006. <http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T/Telomeres.html> 6. Marchetti, et al. “Telomerase Activity as a Prognostic Indicator in State I Non-Small Cell Lung Cancer.” Clinical Cancer Research, 1999. 5: 2077-2081 7. Seimiya, et al. “Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics.” Cancer Cell, 2005. 7:25-37. 8. Shay, et al. “Telomerase and cancer.” Human Molecular Genetics, 2001. Vol. 10 (7): 677-685 9. Stewart, et al. “Telomerase contributes to tumorigenesis by a telomere length-independent mechansim.” PNAS, 2002. Vol. 99 (20): 12606-12611

Telomerase: Cancer and the Philosopher’s Stone