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Genomic instability in cancer and aging

Genomic instability in cancer and aging. Jan Vijg, University of Texas Health Science Center, San Antonio, Texas. A. T. G. C. G. C. Point mutation. Transposition. Deletion/Insertion. Inversion. DNA mutations. Role of genome instability in aging.

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Genomic instability in cancer and aging

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  1. Genomic instability in cancer and aging Jan Vijg, University of Texas Health Science Center, San Antonio, Texas

  2. A T G C G C Point mutation Transposition Deletion/Insertion Inversion DNA mutations

  3. Role of genome instability in aging • Evolutionary logic of genome instability • Evidence for genome deterioration in aging • Association of DNA repair defects with accelerated aging

  4. ln mean fitness Number of mutations Effect of deleterious mutations on fitness in E. coli Elena & Lenski, 1997, Nature 390: 395

  5. “The problem in this theory is that of developing a quantitative measure of mutations in somatic cells” Howard J. Curtis, 1963

  6. LacZ plasmid recovery

  7. Spontaneous mutant frequencies with age in heart and small intestine

  8. Spontaneous mutant frequencies with age in mouse organs

  9. Mutant spectra in vivo and in vitro

  10. Del(-1) Del(-1) Del(-1) Del(-1) Del(-1) Del(-1) A:Tn:n A:Tn:n A:Tn:n A:Tn:n A:Tn:n A:Tn:n G:CC:G G:CC:G G:CC:G G:CC:G G:CC:G G:CC:G G:CT:A G:CA:T G:CA:T G:CA:T G:CA:T G:CA:T G:CA:T G:CT:A G:CT:A G:CT:A G:CT:A G:CT:A G:C  AT at CpG sites Del (-1) at reiterated sites, i.e. a sequence of 3 or more of the same nucleotide Point mutational spectra in organs from Young (3m) and Old (32m) mice Y Brain Heart Liver Spleen Small intestine Mock recovery Mutant frequency (x10-5) Percentage O Lymphoma Mutant frequency (x10-5) Percentage

  11. Mutant frequencies in vivo and in vitro

  12. MEF 6 Growth curve 3% 20% Mutant frequency Total MF Point Mut spectra Size change

  13. Point mutations in MEFs at high and low oxygen

  14. Apoptosis Cell Senescence Transcriptional Interference Mutation Altered Chromatin Genome maintenance and aging Growth & Reproduction Increased Longevity Somatic Maintenance DNA Damage Aging Cancer

  15. Aging in DNA repair-deficient mice Mutant gene Defect Life span (weeks) Aging Phenotype Xpa KO Ercc1 KO Ercc1 HP Complete NER NER and crosslink repair Same 100 3-4 25 None Weight reduction, renal and liver failure, cachexia, sarcopenia, kyphosis, neuronal degeneration Same

  16. Ratio of mRNA expression levels in old v/s young livers (normalized) Ratio of Intensity 72 Arrays 6 Old, 6 Young Animals M = log2(red/green) A = 1/2 log2(red*green) Total Intensity

  17. Ratio of mRNA expression levels in Ercc1-/- knockout v/s wildtype liver M = log2(red/green) A = 1/2 log2(red*green) Over-expressed genes* Under-expressed genes* Significant genes that Overlap with aging* *significant by SAM

  18. Annotation of genes co-expressed in aging and Ercc1 in liver

  19. Mutation accumulation in liver of Ercc1 and Xpa mutant mice 24 weeks 52 weeks

  20. Point mutations in liver of 1-year old Xpa null mice Mutant Frequency (x10-5)

  21. Point mutations in liver of 5mo Ercc1 null mice Mutant Frequency (x10-5)

  22. Conclusions • Different types of mutations accumulate with age in an organ-specific manner • Liver-specific gene expression profile of mice with defects in the repair of double-strand lesions, i.e., Ercc1, is similar to normal aging • DNA repair defects cause shifts in the spectrum of age-accumulating mutations • Genome rearrangements appear to be associated more with aging than with cancer

  23. Acknowledgements Mutation Analysis Rita Busuttil Martijn Dollé Wendy Snyder Microarray Felix Calderon Debbie Muñoz Prakash Nair Bioinformatics Brent Calder John David Garza Paul Lohman Accelerated Genomics Mangkey Bounpheng Nathalie van Orsouw Erasmus University Jan Hoeijmakers Laura Niedernhofer Dana-Farber Cancer Institute Frederick Li Seoul National University Yousin Suh RIVM Harry van Steeg LBNL Judy Campisi

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