Telomeres and Telomerase the internal clock is ticking…

Telomeres and TelomeraseTelomeres and Telomerase

the internal clock is ticking…the internal clock is ticking…

Normal DNA replicationNormal DNA replication

• At the 5’ end, after RNA At the 5’ end, after RNA primer comes off, the DNA primer comes off, the DNA polymerase cannot fill in polymerase cannot fill in the endthe end

• The ends of DNA strands The ends of DNA strands have additional repeated have additional repeated sequences of nucleotides sequences of nucleotides (telomeres)(telomeres)

• Over many DNA Over many DNA replications, these replications, these telomeres shorten until the telomeres shorten until the cell can no longer cell can no longer replicate.replicate.

Without a telomere…Without a telomere…

• Telemeres also can:Telemeres also can:– Protect open ends of chromosomes from enzymatic Protect open ends of chromosomes from enzymatic

digestiondigestion– Anchor chromosomes to nuclear membrane (important Anchor chromosomes to nuclear membrane (important

for chromosome transcription)for chromosome transcription)– Prevent clumping of chromosomes during anaphasePrevent clumping of chromosomes during anaphase





• Open ends of chromosomes are “sticky”; therefore, without Open ends of chromosomes are “sticky”; therefore, without telemeres capping the ends, several linear chromosomes telemeres capping the ends, several linear chromosomes may clump together.may clump together.






• All mammals have TTAGGG as the repeating telomere All mammals have TTAGGG as the repeating telomere sequencesequence






• All mammals have TTAGGG as the repeating telomere All mammals have TTAGGG as the repeating telomere sequencesequence

• Other organisms may have TTGGGG as their sequenceOther organisms may have TTGGGG as their sequence


• Telemeres also can:Telemeres also can:– Protect open ends of chromosomes from enzymatic digestionProtect open ends of chromosomes from enzymatic digestion– Anchor chromosomes to nuclear membrane (important for Anchor chromosomes to nuclear membrane (important for

chromosome transcription)chromosome transcription)– Prevent clumping of chromosomes during anaphasePrevent clumping of chromosomes during anaphase

• Open ends of chromosomes are “sticky”; therefore, without Open ends of chromosomes are “sticky”; therefore, without telemeres capping the ends, several linear chromosomes may telemeres capping the ends, several linear chromosomes may clump together.clump together.

• All mammals have TTAGGG as the repeating telomere sequenceAll mammals have TTAGGG as the repeating telomere sequence

• Other organisms may have TTGGGG as their sequenceOther organisms may have TTGGGG as their sequence

• When telomeres shorten too far, it may either cause altered When telomeres shorten too far, it may either cause altered gene expression or signal for apoptosis.gene expression or signal for apoptosis.

Telomeres and diseasesTelomeres 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 agingDiseases of premature aging

• Down’s SyndromeDown’s Syndrome

• Hutchinson-Gilford progeriaHutchinson-Gilford progeria

• Werner syndromeWerner syndrome

• People with these diseases have demonstrated either People with these diseases have demonstrated either short telomeres or accelerated telomere shortening.short telomeres or accelerated telomere shortening.

– May also be cause of May also be cause of

• Degenerative joint diseaseDegenerative joint disease

• Sensory impairmentSensory impairment– Many cancers take advantage of telomeres tooMany cancers take advantage of telomeres too

TelomeraseTelomerase

• Consists of at least 3 Consists of at least 3 componentscomponents– Telomerase reverse Telomerase reverse

transcriptase (TERT)transcriptase (TERT)– Telomerase-associated Telomerase-associated

protein 1 (TEP1) – protein 1 (TEP1) – regulatory function (? not regulatory function (? not known for sure)known for sure)

– Telomerase RNA subunitTelomerase RNA subunit

• telomerase in actiontelomerase in action

http://faculty.plattsburgh.edu/donald.slish/Telomerase.html

TelomeraseTelomerase

Telomerase and cancer cellsTelomerase 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 Telomerase does NOT cause cancer; it only allows cancer cells to continue proliferation. cells to continue proliferation. – These cells have telomerase reactivated, allowing them These cells have telomerase reactivated, allowing them

to maintain telomere length.to maintain telomere length.

Telomerase and cancer cellsTelomerase 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 Telomerase does NOT cause cancer; it only allows cancer cells to continue proliferation. cells to continue proliferation. – These cells have telomerase reactivated, allowing them These cells have telomerase reactivated, allowing them

to maintain telomere length.to maintain telomere length.

• Cancer cells may activate telomerase through the G1-S Cancer cells may activate telomerase through the G1-S checkpointcheckpoint

• In 30% of human tumors, gene that codes for hTERT is In 30% of human tumors, gene that codes for hTERT is amplified (meaning more likely for telomerase to be active)amplified (meaning more likely for telomerase to be active)

Cancer treatments involving telomeresCancer treatments involving telomeres

• Known as Ptquin8 for short, Known as Ptquin8 for short, this selectively inhibits this selectively inhibits telomerase activitytelomerase activity– Telomerase’s RNA Telomerase’s RNA

template is rich in guanine.template is rich in guanine.– Platinum based drugs such Platinum based drugs such

as cisplatin, carboplatin, as cisplatin, carboplatin, and Ptquin8 have a high and Ptquin8 have a high affinity for these guanines affinity for these guanines in the N7 position.in the N7 position.

– Does not completely inhibit Does not completely inhibit telomerase, but enough to telomerase, but enough to destabilize telomeric destabilize telomeric homeostasishomeostasis

Cis-[Pt(Cl)Cis-[Pt(Cl)22(pyridine)(5-SO(pyridine)(5-SO33H-isoquinoline)] complexH-isoquinoline)] complex

Cancer treatments involving telomeresCancer treatments involving telomeres

• Ptquin8 also will not interfere Ptquin8 also will not interfere with other genomic DNAwith other genomic DNA– However, Ptquin8 works However, Ptquin8 works

because of genetic because of genetic alterationsalterations

• Active in low concentrations Active in low concentrations (10(10-9-9 to 10 to 10-7-7 M) M)

• No aspecific cytotoxicityNo aspecific cytotoxicity– Not as harmful to other Not as harmful to other

healthy cells like healthy cells like chemotherapy ischemotherapy is

• Overall, a good cancer Overall, a good cancer treatment optiontreatment option

Cis-[Pt(Cl)Cis-[Pt(Cl)22(pyridine)(5-SO(pyridine)(5-SO33H-isoquinoline)] complexH-isoquinoline)] complex

Telomeres and agingTelomeres and aging

• Cells generally divide 60-100x during lifespanCells generally divide 60-100x during lifespan

• Once telomeres shorten enough, cell enters Once telomeres shorten enough, cell enters senescence (aging)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 treatmentTelomerase as anti-aging treatment

• Abnormally reactive in cancer cellsAbnormally reactive in cancer cells

• Maintaining telomere length with telomerase in Maintaining telomere length with telomerase in normal cells could lead to cancernormal cells could lead to cancer

• Needs cells to undergo division, some don’t Needs cells to undergo division, some don’t (muscle and nerve)(muscle and nerve)

• Overall aging of body (mechanical stress, etc.) Overall aging of body (mechanical stress, etc.) cannot be overcome simply by activating cannot be overcome simply by activating telomerasetelomerase– How much of a role does telomerase actually How much of a role does telomerase actually

play?play?

Telomerase as a diagnostic toolTelomerase as a diagnostic tool

• Could be used as a marker for cancer diagnostics, Could be used as a marker for cancer diagnostics, prognosis, patient monitoring, and screeningprognosis, patient monitoring, and screening

• Telomerase activity indicative of cancer cellsTelomerase activity indicative of cancer cells

The future researchThe future research

• Cells from diseased tissue can be telomerase-Cells from diseased tissue can be telomerase-immortalizedimmortalized– Function comparably well to non-immortalized Function comparably well to non-immortalized

counterpartscounterparts– Explore mechanism of diseaseExplore mechanism of disease– Develop interventions for treatment and Develop interventions for treatment and

preventionprevention


• Wound healingWound healing

• Tissue regeneration (ex: burn victims)Tissue regeneration (ex: burn victims)– Problem: How do you stop treated cells from Problem: How do you stop treated cells from

becoming cancerous?becoming cancerous?


• Age related diseasesAge related diseases– Atherosclerosis, macular degeneration (eye)Atherosclerosis, macular degeneration (eye)

• Take patient’s cells, manipulate and rejuvenate Take patient’s cells, manipulate and rejuvenate them, then reinsert them into their bodythem, then reinsert them into their body– Expansion of specific immune cells or nerve cell Expansion of specific immune cells or nerve cell

precursorsprecursorsPossible treatementsPossible treatements

Immune deficiencies or neurodegenerative Immune deficiencies or neurodegenerative diseasesdiseases

• Continued cancer researchContinued cancer research– Peptide Epithalon and how it induces telomerase activityPeptide Epithalon and how it induces telomerase activity

Works citedWorks cited

• Altshuler, M.L., S.E. Severin, and A.I. Glukhov. “The Tumor Cell and Telomerase.” Altshuler, M.L., S.E. Severin, and A.I. Glukhov. “The Tumor Cell and Telomerase.” Biochemistry Biochemistry (Moscow)(Moscow). Vol 68, No. 12, 2003, 1275-1283.. Vol 68, No. 12, 2003, 1275-1283.

• Clark, William R. Clark, William R. A Means to an End: The Biological Basis of Aging and DeathA Means to an End: The Biological Basis of Aging and Death. Oxford University . Oxford University Press, New York. 1999.Press, New York. 1999.

• Colangelo, D., A. L. Ghiglia, I. Viano, G. Cavigiolio, and D. Osella. “Cis-[Pt(Cl)2(pyridine)(5-SO3H-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.” isoquinoline)] complex, a selective inhibitor of telomerase enzyme.” BioMetalsBioMetals 1616: 553-560, 2003. : 553-560, 2003.

• Li, H. and J-P Liu. “Signaling on telomerase: a master switch in cell aging and immortalization.” Li, H. and J-P Liu. “Signaling on telomerase: a master switch in cell aging and immortalization.” BiogerontologyBiogerontology 3:3: 107-116, 2002. 107-116, 2002.

• http://http://www.geron.comwww.geron.com//

• http://www.swmed.edu/home_pages/cellbio/shay-wright/research/sw_research.htmlhttp://www.swmed.edu/home_pages/cellbio/shay-wright/research/sw_research.html

http://www.geron.com/



http://www.swmed.edu/home_pages/cellbio/shay-wright/research/sw_research.html

Documents

Telomeres and Telomerase the internal clock is ticking…