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Aging and gene expression – Alterations of the genome due to aging

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011.

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Aging and gene expression – Alterations of the genome due to aging

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Krisztián Kvell Molecular and Clinical Basics of Gerontology – Lecture 22 Aging and geneexpression –Alterations of thegenomeduetoaging

  3. Telomere sequence andtelomerase function Telomerase A C C A A U C RNA template T G G T T A DNA G Nucleotides

  4. Telomeres as biological clocks • Most favoredclock, butcauseor marker? • Sequence: TTAGGG hexanucleotide> 1000x • Polymeraseleavesgapwitheveryreplication • Oxidativestressacceleratestelomerelossrate

  5. Factors influencing telomere loss rate • Telomeresformterminalloopsforstability • Role of TRF2 intelomerestability • Issue of telomerelengththreshold • Issue of telomerelossrate vs. stressrate

  6. Changes in telomere length Extending the length of a telomere Embyonic stem cells Adult stem cells Chromosome Short end of DNA New DNA Telomere long Telomere short T T A G G G T T A G G G Active telomerase Telomerase inactive or absent A A U C C C A A U C C C A A T C C C A A T C RNA template T T A G G G Telomerase DNA polymerase A A T C C C Telomere is repetitive DNA sequence

  7. Slowing, reversing telomere shortening • Counteracting (oxidative) stressconditions • Telomeraseactivityincreasestelomerelength • ALT: alternativetelomerelengthening

  8. Significance of telomere in cancer Telomerase reactivation Telomere lenght Telomere crisis Normal tissue Hyperplasia Carcinoma in situ Invasive cancer Number of aberrations Genome instability Further evolution Loss of telomere function

  9. Further clocks ticking • Solublefactors / cellnon-autonomousspreading • Pinealclock, role of melatonin • Circadianclockmechanisms • DNA methylation, acetylation, de-acetylation

  10. Genomic instability in progeria types • Werner-syndrome • Cockaynesyndrome • Hutchinson-Guilfordprogeria • Xeroderma pigmentosum

  11. Werner syndrome • Homozygousrecessive (skin, cataract, diabetes mellitus osteoporosis) • WRN protein (anti-recombinase, helicase, removesrecombination and repairintermediates) • Defectivetranscription (50%) • Relationwith p53 (attenuatedapoptosis) • Increasedtelomerelossrate

  12. Cockayne syndrome • Raresegmentalprogeria (dwarfism, photosensitivity, neurologicaldegeneration etc.) • Defectintranscriptioncoupledrepair (TCR) • Defective 8-oxodG excision (50%) • Subtypes: CS-A, CS-B • Global genomerepair (GGR) is proficient

  13. Hutchinson-Guilford progeria syndrome • Lamin A mutation (nuclearenvelopefragility) • Primerilyaffectsmesenchymaltissues • HGPS cellshavedecreasedstressresistence • Rapid progeria, prematuredeath

  14. DNA damage: causes, results I Reactive oxygen species (ROS) DNA REPAIR (limited synthesis:small fragments) Replication errors X rays UV light Cell cycle arrest (Apoptosis) Mutations Cancer and genetic diseases Alkylating agents Spontaneous reactions

  15. Oxidative DNA damage • > 10,000 DNA lesions / cell / day • A variety of DNA damagetypes (> 50 types) • 5 distinctivegroups • Oxidizedpurines • Oxidizedpyrimidines • Abasicsites • Single-strandbreaks • Double-strandbreaks

  16. DNA damage: causes, results II Metabolism Exogenus DNA damage Stochastic DampenedGH/IGF axis Cellular responses(apoptosis,senescence) Mutations, epi-mutations Regulated Improved survival Tissue atrophy, lost regeneration Altered regulatory circuits Tissue/organ functional decline, degenerative or hyperplastic disease

  17. Oxidative DNA damage repair types I • Baseexcisionrepair (BER) is most important, subtypes: AP endonucleaseorlyaserepair • Removal of oxidizedpurines (twotypesoflesions: 8-oxodG and formamido-pyrimidines) • Removal of oxidizedpyrimidines (strongblock, stronglycytotoxic) • Repair of abasicsites (most frequent) by AP endonucleases

  18. Oxidative DNA damage repair types II • Repair of strand breaks (single-strand breaks occur 10x more frequently than doubles) • Limited mitochondrial DNA repair (nuclearencodedproteins of OGG1, POLG) • Nucleotideexcisionrepair (NER) that is transcription-coupledrepair of activegenes

  19. Genes related to oxidative DNA damage repair • Defect is lethal: APE1, FEN1, POLB, LIG1, LIG3, XRCC1 • Defect is viable: OGG1, NTHL1, MYH, ADPRT • Severitynot tested: NEIL1, 2, 3, TDG, SMUG1, APE2

  20. Oxidative DNA damage repair and aging • Elevatedcancerfrequencies • Werner syndrome (anti-recombinase) • Cockaynesyndrome (TCR) • XPD and XPA (repairdeficiency) • Baseexcisionrepair (BER) defect is lethal • Back-uprepairpathways

  21. Non-oxidative DNA damage • Depurination and depyrimidination • Deamination • Single-strandbreaks • Spontaneousmethylation • Glycation • Cross-linking

  22. Non-oxidative protein damage • Biosyntheticerrors • Transcriptionalerrors • Translationalerrors • Racemization and isomerization • Deamidation (asparagine and glutamine) • Reactivecarbonylgroups (non-oxidative) • Serinedephosphorylation

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