Telomerase: Cancer and the Philosopher’s Stone
Sapana Vora
1 March 2007
Biology 445
Table of Contents
Chapter 1: TelomeresChapter 2: Telomerase: FunctionChapter 3: Telomerase: StructureChapter 4: Telomerase and CancerEpilogueBibliography
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
telomeretelomere
Human telomeric repeat sequence: 5’- TTAGGG -3’
Page 1
DNA Replication Anyone?
RNA primer for Okazaki fragment
DNA PolymeraseLeading strand
Lagging strandSite of next
primer
5’
3’
5’
3’3’
5’
Page 2
Telomeres during DNA Replication
Lagging strand Okazaki fragments leave unfinished 5’ ends
No complementary strand DNA degrades
Image: http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T/Telomeres.html Page 3
Chromosomal Alzheimer’s in Action
Round 305’3’
3’5’
Round 605’3’
3’5’
Round 905’3’
3’5’
Round 15’3’
3’5’
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 chromosomesProtects 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
Shay, J. W. et al. Hum. Mol. Genet. 2001 10:677-685; doi:10.1093/hmg/10.7.677
Immunohistochemical localization of hTERT protein in normal and cancer cells
Telomerase Activity in Cancer
Page 10
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 305’3’
3’5’
Round 605’3’
3’5’
Round 905’3’
3’5’
Round 15’3’
3’5’
Page 12
Cancer Cells Do It Differently
Round 15’3’
3’5’
Round 305’3’
3’5’
Round 605’3’
3’5’
Round 905’3’
3’5’
Page 13
Epilogue: Cancer Therapeutics?
Telomerase is expressed almost exclusively in malignant cells…
But…Telomere length varies in different
cancer cellsALT (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