Telomeres and Telomerase the internal clock is ticking…

Normal DNA replication At the 5’ end, after RNA primer comes off, the DNA polymerase cannot fill in the end At the 5’ end, after RNA primer comes off, the DNA polymerase cannot fill in the end The ends of DNA strands have additional repeated sequences of nucleotides (telomeres) The ends of DNA strands have additional repeated sequences of nucleotides (telomeres) Over many DNA replications, these telomeres shorten until the cell can no longer replicate. Over many DNA replications, these telomeres shorten until the cell can no longer replicate.

Without a telomere… Telemeres also can: Telemeres also can: –Protect open ends of chromosomes from enzymatic digestion –Anchor chromosomes to nuclear membrane (important for chromosome transcription) –Prevent clumping of chromosomes during anaphase

Without a telomere… Telemeres also can: Telemeres also can: –Protect open ends of chromosomes from enzymatic digestion –Anchor chromosomes to nuclear membrane (important for chromosome transcription) –Prevent clumping of chromosomes during anaphase Open ends of chromosomes are “sticky”; therefore, without telemeres capping the ends, several linear chromosomes may clump together. Open ends of chromosomes are “sticky”; therefore, without telemeres capping the ends, several linear chromosomes may clump together.

Without a telomere… Telemeres also can: Telemeres also can: –Protect open ends of chromosomes from enzymatic digestion –Anchor chromosomes to nuclear membrane (important for chromosome transcription) –Prevent clumping of chromosomes during anaphase Open ends of chromosomes are “sticky”; therefore, without telemeres capping the ends, several linear chromosomes may clump together. Open ends of chromosomes are “sticky”; therefore, without telemeres capping the ends, several linear chromosomes may clump together. All mammals have TTAGGG as the repeating telomere sequence All mammals have TTAGGG as the repeating telomere sequence

Without a telomere… Telemeres also can: Telemeres also can: –Protect open ends of chromosomes from enzymatic digestion –Anchor chromosomes to nuclear membrane (important for chromosome transcription) –Prevent clumping of chromosomes during anaphase Open ends of chromosomes are “sticky”; therefore, without telemeres capping the ends, several linear chromosomes may clump together. Open ends of chromosomes are “sticky”; therefore, without telemeres capping the ends, several linear chromosomes may clump together. All mammals have TTAGGG as the repeating telomere sequence All mammals have TTAGGG as the repeating telomere sequence Other organisms may have TTGGGG as their sequence Other organisms may have TTGGGG as their sequence

Without a telomere… Telemeres also can: Telemeres also can: –Protect open ends of chromosomes from enzymatic digestion –Anchor chromosomes to nuclear membrane (important for chromosome transcription) –Prevent clumping of chromosomes during anaphase Open ends of chromosomes are “sticky”; therefore, without telemeres capping the ends, several linear chromosomes may clump together. Open ends of chromosomes are “sticky”; therefore, without telemeres capping the ends, several linear chromosomes may clump together. All mammals have TTAGGG as the repeating telomere sequence All mammals have TTAGGG as the repeating telomere sequence Other organisms may have TTGGGG as their sequence Other organisms may have TTGGGG as their sequence When telomeres shorten too far, it may either cause altered gene expression or signal for apoptosis. When telomeres shorten too far, it may either cause altered gene expression or signal for apoptosis.

Telomeres and diseases Shortened telomeres may be the culprit to such diseases as: Shortened telomeres may be the culprit to such diseases as: –Diseases of premature aging Down’s Syndrome Down’s Syndrome Hutchinson-Gilford progeria Hutchinson-Gilford progeria Werner syndrome Werner syndrome People with these diseases have demonstrated either short telomeres or accelerated telomere shortening. People with these diseases have demonstrated either short telomeres or accelerated telomere shortening. –May also be cause of Degenerative joint disease Degenerative joint disease Sensory impairment Sensory impairment –Many cancers take advantage of telomeres too

Telomerase Consists of at least 3 components Consists of at least 3 components –Telomerase reverse transcriptase (TERT) –Telomerase-associated protein 1 (TEP1) – regulatory function (? not known for sure) –Telomerase RNA subunit telomerase in action telomerase in action telomerase in action telomerase in action

Telomerase

Telomerase and cancer cells Active telomerase found in 90% of human tumors. Active telomerase found in 90% of human tumors. Telomerase does NOT cause cancer; it only allows cancer cells to continue proliferation. Telomerase does NOT cause cancer; it only allows cancer cells to continue proliferation. –These cells have telomerase reactivated, allowing them to maintain telomere length.

Telomerase and cancer cells Active telomerase found in 90% of human tumors. Active telomerase found in 90% of human tumors. Telomerase does NOT cause cancer; it only allows cancer cells to continue proliferation. Telomerase does NOT cause cancer; it only allows cancer cells to continue proliferation. –These cells have telomerase reactivated, allowing them to maintain telomere length. Cancer cells may activate telomerase through the G1-S checkpoint Cancer cells may activate telomerase through the G1-S checkpoint In 30% of human tumors, gene that codes for hTERT is amplified (meaning more likely for telomerase to be active) In 30% of human tumors, gene that codes for hTERT is amplified (meaning more likely for telomerase to be active)

Cancer treatments involving telomeres Known as Ptquin8 for short, this selectively inhibits telomerase activity Known as Ptquin8 for short, this selectively inhibits telomerase activity –Telomerase’s RNA template is rich in guanine. –Platinum based drugs such as cisplatin, carboplatin, and Ptquin8 have a high affinity for these guanines in the N7 position. –Does not completely inhibit telomerase, but enough to destabilize telomeric homeostasis Cis-[Pt(Cl) 2 (pyridine)(5-SO 3 H-isoquinoline)] complex

Cancer treatments involving telomeres Ptquin8 also will not interfere with other genomic DNA Ptquin8 also will not interfere with other genomic DNA –However, Ptquin8 works because of genetic alterations Active in low concentrations (10 -9 to M) Active in low concentrations (10 -9 to M) No aspecific cytotoxicity No aspecific cytotoxicity –Not as harmful to other healthy cells like chemotherapy is Overall, a good cancer treatment option Overall, a good cancer treatment option Cis-[Pt(Cl) 2 (pyridine)(5-SO 3 H-isoquinoline)] complex

Telomeres and aging Cells generally divide x during lifespan Cells generally divide x during lifespan Once telomeres shorten enough, cell enters senescence (aging) Once telomeres shorten enough, cell enters senescence (aging) Internal “clock” for cellular aging? Internal “clock” for cellular aging? Telomerase would essentially reset the “clock” Telomerase would essentially reset the “clock”

Telomerase as anti-aging treatment Abnormally reactive in cancer cells Abnormally reactive in cancer cells Maintaining telomere length with telomerase in normal cells could lead to cancer Maintaining telomere length with telomerase in normal cells could lead to cancer Needs cells to undergo division, some don’t (muscle and nerve) Needs cells to undergo division, some don’t (muscle and nerve) Overall aging of body (mechanical stress, etc.) cannot be overcome simply by activating telomerase Overall aging of body (mechanical stress, etc.) cannot be overcome simply by activating telomerase –How much of a role does telomerase actually play?

Telomerase as a diagnostic tool Could be used as a marker for cancer diagnostics, prognosis, patient monitoring, and screening Could be used as a marker for cancer diagnostics, prognosis, patient monitoring, and screening Telomerase activity indicative of cancer cells Telomerase activity indicative of cancer cells

The future research Cells from diseased tissue can be telomerase- immortalized Cells from diseased tissue can be telomerase- immortalized –Function comparably well to non-immortalized counterparts –Explore mechanism of disease –Develop interventions for treatment and prevention

The future research Wound healing Wound healing Tissue regeneration (ex: burn victims) Tissue regeneration (ex: burn victims) –Problem: How do you stop treated cells from becoming cancerous?

The future research Age related diseases Age related diseases –Atherosclerosis, macular degeneration (eye) Take patient’s cells, manipulate and rejuvenate them, then reinsert them into their body Take patient’s cells, manipulate and rejuvenate them, then reinsert them into their body –Expansion of specific immune cells or nerve cell precursors  Possible treatements  Immune deficiencies or neurodegenerative diseases Continued cancer research Continued cancer research –Peptide Epithalon and how it induces telomerase activity

Works cited Altshuler, M.L., S.E. Severin, and A.I. Glukhov. “The Tumor Cell and Telomerase.” Biochemistry (Moscow). Vol 68, No. 12, 2003, Altshuler, M.L., S.E. Severin, and A.I. Glukhov. “The Tumor Cell and Telomerase.” Biochemistry (Moscow). Vol 68, No. 12, 2003, Clark, William R. A Means to an End: The Biological Basis of Aging and Death. Oxford University Press, New York Clark, William R. A Means to an End: The Biological Basis of Aging and Death. Oxford University Press, New York Colangelo, D., A. L. Ghiglia, I. Viano, G. Cavigiolio, and D. Osella. “Cis-[Pt(Cl)2(pyridine)(5-SO3H-isoquinoline)] complex, a selective inhibitor of telomerase enzyme.” BioMetals 16: , Colangelo, D., A. L. Ghiglia, I. Viano, G. Cavigiolio, and D. Osella. “Cis-[Pt(Cl)2(pyridine)(5-SO3H-isoquinoline)] complex, a selective inhibitor of telomerase enzyme.” BioMetals 16: , Li, H. and J-P Liu. “Signaling on telomerase: a master switch in cell aging and immortalization.” Biogerontology 3: , Li, H. and J-P Liu. “Signaling on telomerase: a master switch in cell aging and immortalization.” Biogerontology 3: ,