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The Mutability and Repair of DNA

The Mutability and Repair of DNA. (transition). (transversion). purine. pyrimidine. Replication errors and their repair. The nature of mutations: Point mutation. 1. Switch of one base for another:. 2. insertion or deletion of a nucleotide. Drastic changes in DNA. Deletion Insertion

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The Mutability and Repair of DNA

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  1. The Mutability and Repair of DNA

  2. (transition) (transversion) purine pyrimidine Replication errors and their repair The nature of mutations: Point mutation 1. Switch of one base for another: 2. insertion or deletion of a nucleotide

  3. Drastic changes in DNA Deletion Insertion Rearrangement of chromosome By insertion of a transposon, or aberrant actions of recombination Process.

  4. Some replication errors escape proofreading

  5. Mismatch repair removes errors escape proofreading 2. The system must correct the mismatch accurately. 1. It must scan the genome. Scan DNA MutL activate MutH Distortion in the backbone Embracing mismatch; Inducing a kick in DNA; Conformational change in MutS itself Nicking is followed by Helicase (UvrD) and one of exonucleases (III)

  6. DNA methylation to recognize the parental strain Once activated, MutH selectively nicks the Unmethylated strand.

  7. Directionality in mismatch repair

  8. Mismatch repair system in Eukaryotics MutS MutL E. coli MSH (MutS homolog) MLH or PMS Eukaryotics Hereditary nonpolyposis colorectal cancer (mutations in human homologes of Muts and MutL)

  9. DNA damage Radiation, chemical mutagens, and spontaneous damage spontaneous damage due to hydrolysis and deamination Deamination converts adenine to hypoxanthine, base pair with C Deamination converts Guanine to xanthine, base with C but only two H bonds deamination Base pair with A depurination

  10. DNA damage spontaneous damage to generate natural base deamination Methylated Cs are hot spot for spontaneous mutation in vertebrate DNA

  11. Damaged by alkylation and oxidation Alkylation at the oxygen of carbon atom 6 of G : O6-metylguanine, often mispairs with T. Oxidation of G generates oxoG, it can mispair with A and C. a G:C to T:A transversion is one of the most common mutation in human cancers.

  12. Gamma radiation and X-rays • Cause double-strand breaks in the DNA, which are difficult to repair. • Ionizing radiation and agents like bleomycin that cause DNA to break are said to be clastogenic (p245).

  13. DNA damage by UV Thymine dimer These linked bases are incapable of base-pairing and cause DNA polymerase to stop.

  14. Mutations caused by base analogs and intercalating agents Base analogs Thymine analog Analogs mispair to cause mistakes during replication

  15. Mutations caused by intercalating agents Intercalating agents flat molecules Causing addition or deletion of bases during replication

  16. Repair of DNA Damage: DNA repair system Excision repair systems: the damaged nucleotide is not repaired but removed from the DNA, the other undamaged strand serves as a template for reincorporation of the correct nt by DNA polymerase Recombination repair: both strands are damaged. Sequence information is retrieved from a second undamaged copy of the chromosome.

  17. Direct reversal of DNA damage photoreactivation Capture energy from light breaking covalent bond To its own cytosine O6-metylguanine

  18. Base excision repair DNA glycosylases are lesion-specific and cells have multiple DNA glycosylases 1. Uracil glycosylase 2. Another specific glycosylase is responsible for removing oxoG AP: apurinic or apyrimidinic

  19. Base excision repair If a damaged base is not removed by base excision before DNA replication: a fail-safe system oxoG:A repair

  20. Nucleotide Excision Repair Recognizing distortions to the shape of the DNA (thymine dimer or bulky chemical adduct) 4-5 nt away from 3’ UvrA detecting distortion 8 nt away from 5’ UvrB melting DNA In E.coli: 4 proteins involved

  21. Nucleotide Excision Repair The principles of nucleotide excision repair in higher cells is much the same as in E. coli but us moer complicated, involving 25 or more polypeptides. The UVR proteins are needed to mend damage from UV light; Mutants of uvr genes are sensitive to UV light, and lack the capacity to remove T-T or T-C adducts. In human, xeroderma pigmentosum patients have mutations in seven genes (XP genes). These XP proteins are corresponding to proteins involved in nucleotide excision repair.

  22. Transcription-coupled repair Involves recruitment to the stalled RNA polymerase of nucleotide excision repair proteins It focuses repair on genes being actively transcribed. TFIIH unwinds the DNA template during the initiation of transcription. Subunits of TFIIH include the DNA helix-opening proteins XPA and XPD.

  23. Translesion DNA synthesis: although are template dependent, the synthesis in a manner that is independent of base pairing obstacles to progression of the DNA polymerase (or AP site) Complex of proteins UmuC and D’ (Y-family of DNA polymerase)

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