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18th Lecture TELOMERES &TELOMERASE Gihan E-H Gawish, MSc, PhD Ass. Professor Molecular Genetics and Clinical Biochemistry KSU TELOMERES What are they? Why are they important? Telomere shortening and the end-replication problem Telomerase Telomere hypothesis of aging Telomeres Animation Ends of linear chromosomes Centromere Telomere Telomere Repetitive DNA sequence (TTAGGG in vertebrates) Specialized proteins Form a 'capped' end structure Telomeres 'cap' chromosome ends TELOMERE STRUCTURE 5’ 3’ Telomeric t loop 5' 3' NUCLEAR MATRIX Telomeric proteins: TRF1 TRF2 TIN2 RAP1 TANKS 1,2 POT1 etc Why are telomeres important? Telomeres allow cells to distinguish chromosomes ends from broken DNA Stop cell cycle! Repair or die!! Homologous recombination (error free, but need nearby homologue) Non-homologous end joining (any time, but error-prone) TELOMERASE: Key to replicative immortality Enzyme (reverse transcriptase) with RNA and protein components Adds telomeric repeat DNA directly to 3' overhang (uses its own RNA as a template) Vertebrate repeat DNA on 3' end: TTAGGG Telomerase RNA template: AAUCCC TELOMERASE: Key to replicative immortality + TELOMERASE Overcomes telomere shortening and the endreplication problem Expressed by germ cells, early embryonic cells Not expressed by most somatic cells (human) May be expressed by some stem cells, but highly controlled Expressed by 80-90% of cancer cells Remaining still need to overcome the end replication problem; do so by recombinational mechanisms -ALT (alternative lengthening of telomeres) mechanisms Telomere Length and Cell Division Potential Telomere Length (humans) 20 10 Germ Cells (Telomerase Positive) Normal Somatic Cells + Telomerase (Telomerase Negative) Cellular (Replicative) Senescence Number of Doublings HOWEVER, CELLS THAT EXPRESS TELOMERASE STILL UNDERGO SENESCENCE (E.G., IN RESPONSE TO DNA DAMAGE, ONCOGENES, ETC.) Animation Inducers of cellular senescence Cell proliferation (short telomeres) DNA damage Oncogenes Strong mitogens/ stress Potential Cancer Causing Events Telomerase: Biomedical uses Expand cells for replacement therapies (burns, joint replacements, etc) Telomerase inhibitors to selectively kill cancer cells The telomere hypothesis of aging Telomeres shorten with each cell division and therefore with age Short telomeres cause cell senescence and senescent cells may contribute to aging HYPOTHESIS: Telomere shortening causes aging and telomerase will prevent aging TRUE OR FALSE? The telomere hypothesis of aging Telomere length is not related to life span (mice vs human; M musculus vs M spretus) Telomeres contribute to aging ONLY if senescent cells contribute to aging Telomerase protects against replicative senescence but not senescence induce by other causes SUMMARY -click to find the attached fileTelomeres are essential for chromosome stability Telomere shortening occurs owing to the biochemistry of DNA replication Short telomeres cause replicative senescence (other senescence causes are telomere-independent) Telomerase prevents telomere shortening and replicative senescence The telomere hypothesis of aging depends on the cellular senescence hypothesis of aging