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DNA Repair

DNA Repair. Uracil-DNA Glycosylase. DNA is continually assaulted by damaging agents (oxygen free radicals, ultraviolet light, toxic chemicals). Fortunately, the cell has multiple mechanisms to identify and correct mutations. Yeasts have 50 different enzymes involved in DNA repair.

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DNA Repair

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  1. DNA Repair Uracil-DNA Glycosylase

  2. DNA is continually assaulted by damaging agents (oxygen free radicals, ultraviolet light, toxic chemicals). Fortunately, the cell has multiple mechanisms to identify and correct mutations.

  3. Yeasts have 50 different enzymes involved in DNA repair.

  4. Damage occurs in the form of deletions and mutations (changes in the sequence of DNA bases that make up the genetic code).

  5. The DNA repair process may be a major factor in aging, health, and longevity.

  6. An animal's ability to repair certain types of DNA damage is directly related to the life span of its species

  7. Genetic defects in DNA repair are associated with genetic or familial susceptibility to cancer. Figure from theDuke University Medical Center and the Graduate Program in Molecular Cancer Biology http://mcb.mc.duke.edu/ Cell nuclei and chromosomes from a human brain tumor

  8. Mitochondrial DNA is more susceptible to damage than nuclear DNA. Furthermore, mitochondrial DNA damage increases exponentially with age. Several diseases that appear late in life, including late-onset diabetes, have been traced to defects in mitochondria.

  9. Causes of Mutations DNA replication Spontaneous depurination and deamination UV light Oxidation Chemically induced

  10. DNA Mismatch Repair (E. coli) How does the cell know which strand to repair? Deoxyadenosine methylase (dam) Old DNA methylated New DNA unmethylated Mismatch repair system cuts unmethylated DNA In eukaryotes the recognition may be nicks.

  11. DNA Repair and Cancer Do humans have a mismatch repair system? hMSH, human Mut S Homolog hMLH, human Mut L Homolog What phenotype would be expected from a mutation in hMSH or hMLH? Hereditary nonpolyposis colon cancer (HNPCC), Lynch syndrome II

  12. Depurination and Deamination Loose A or G Loose NH2 groups from C (forms U)

  13. Base-Excision Repair Pathway All organisms contain a specific repair pathway which removes uracil from DNA.

  14. DNA Damage From UV Light

  15. Ionizing radiation causes three types of damage to DNA Single-strand breaks - mostly sealed by DNA ligase so don't contribute to lethality Double-strand breaks - often lethal because can't be resealed by ligase so degraded by nucleases Alteration of bases - this type of oxidative damage is usually lethal because forms a replication barrier at that site

  16. uvrABCD Repair System What would be the phenotype in humans from an accumulation of thymine dimers in somatic cells? What would be the phenotype in humans from mutations in uvrABCD genes? Xeroderma Pigmentosum (XP)

  17. Disorders Associated with Defective DNA Repair Xeroderma pigmentosum (XP) • Skin photosensitivity; Early onset skin cancer Cockayne Syndrome • Dwarfism; Precociously senile appearance • Sensitivity to sunlight Bloom Syndrome • Dwarfism, low-birth-weight type; • Life-threatening infections • Predisposition to neoplasia

  18. Helicase: Bloom syndrome (genomic instability in somatic cells, leads to telangiectatic facial erythema, photosensitivity, dwarfism and other abnormalities) BRCA1 DNA repair proteinBreast and Ovarian cancer, early onset MSH2 DNA repair proteinHereditary non-polyposis colon cancer

  19. Mutations in DNA repair genes lead to an increase in the frequency of other mutations.

  20. Ataxia-Telangiectasia Approximately 10% of children diagnosed with AT will develop a malignancy in childhood or early adulthood. The gene defect in AT patients allows the formation of a much higher level of chromosome translocations.

  21. Transcription in eukaryotes Transcription occurs in nucleus, translation occurs in cytoplasm: RNA must move across nuclear membrane.

  22. Regulation involves multiple enzymes & proteins -30 'TATAAAA' (Hogness box) promoter -50 ~ -500 enhancer sequences control rate

  23. Post-transcriptional processing poly-A 'tail' (5'-AAAAAA-etc-AAAAAA-3') added to 3' end (Fig.12.10a) 7mG 'cap'(7-methyl guanosine, 7mG) added to 5' end splicing of heterogeneous nuclear RNA(hnRNA) (Fig.12.10b) up to 90% of transcript is removed exonsare retained ("expressed") intronsare removed ("intervening") 10 ~ 20 exons / 'gene'

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