生物化学原理教学（杨荣武）Chapter34 DNA damage, repair and mutation.pptVIP

Outline DNA Damages DNA Repair Direct repair Excision repair Double-stranded break repair Damage bypass DNA mutation Types and Consequences of Mutations Mutagens Reverse mutation and Suppressor mutation Relationship of Mutagen and Carcinogen DNA is Stable, but fragile What Factors Alter DNA Integrity? Endogenous Cellular Factors Environmental -e.g. chemicals, pollution, UV light Disease treatments -e.g. ionizing radiation, chemotherapy Endogenous Cellular Factors Replication errors e.g. imbalance in the nucleotide pools -result in mismatch DNA instability deamination of bases depurination/depyrimidination of DNA loss of base Reactive oxygen species DNA, protein and lipid oxidation Depurination/Depyrimidination Depurination occurs more rapidly than depyrimidination Results in a deoxyribose without a base (AP site) E.coli :1 depurination/ genome/ doubling Thermus Thermophilus :300 depurinations/ genome/doubling Mammalian cell:10, 000 depurinations/ genome/ doubling Reactive oxygen species Produced by normal cellular metabolism Mitochondria utilize ~85% O2 in cell and are a major source of ROS Damage DNA, protein and lipid. Some forms in cell are: Hydrogen peroxide (H2O2) Superoxide radical (O2?-) Nitric oxide (?NO) Hydroxyl radical (HO?) Peroxynitrite (O=NOO-) Alkyl hydroperoxide (ROOH) Alkoxyl radical (RO?) Environmental (Exogenous) factors Chemical Agents (1) Natural Chemicals Aflatoxins - nuts (2) Man-made Chemicals Benzopyrene - cigarette smoke Chemotherapy drugs - cisplatin Physical Agents (1) Sun and tanning booth lamps (UV) (2) Ionizing Radiation γ-rays x-rays Types of DNA Damage Base modification Loss of bases - abasic or apurinic sites Replication errors: Mismatch Strand breakage Protein-DNA cross-links DNA-DNA cross-links Tautomerization leads to DNA mismatch keto?enol common bp with tautomers: AC, AA, GT, AG DNA is Stable, but fragile Failure to repair causes mutations Can interfer