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