Orren IBS602-012710

Orren IBS602-012710 - IBS602 Lectures #6 and 7 DNA Damage...

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Unformatted text preview: IBS602 Lectures #6 and 7 DNA Damage and Repair 1/27/10, 1/29/10 Chapter 10 David Orren Graduate Center for Toxicology 356 HSRB email: dkorre2@uky.edu Phone: 3-3612 Integrity of DNA and the information it carries is constantly being challenged DNA provides the information for: Perpetuation of species Organismal development Cellular function For human cells, 3.4 10 9 bp (6.8 10 9 nucleotides) must be replicated and repaired faithfully DNA is a very reactive molecule Subject to structural/chemical change caused by: Endogenous processes Exogenous agents (Environmental exposures) Cells have multiple enzymatic repair systems to restore the correct DNA structure and sequence Some damage escapes or overwhelms these surveillance systems Mutation generation Initiation (and progression) of carcinogenesis Origin of hereditary/genetic diseases Cell death (or cell cycle exit/senescence) Involvement in some aging phenotypes DNA Damage Any chemical/structural deviation from the normal Watson-Crick character of continuous double-stranded chromosomes * not including intermediates formed during normal DNA metabolism Most types of damage fit into one of two major categories (based on primary DNA structure) 1. Alter normal base chemistry and/or A:T and G:C base-pairing specificity (mismatches, base lesions ) 2. Disrupt continuity of one or both strands of the phosphodiester backbone (strand breaks ) DNA damage definitions Lesion: any type of DNA damage Mismatch: non Watson-Crick base pair Adduct: foreign chemical moiety covalently linked to DNA Alkylation damage: covalent adduction of DNA via carbon linkage (usually) to base Oxidative DNA damage: due to ROS, results in many different types of lesions Photoproduct: lesion generated by exposure to UV irradiation Intrastrand crosslink: covalent linkage between nucleotides on the same strand Interstrand crosslink: covalent linkage between nucleotides on opposite strands Endogenous damage: generated without influence from outside the cell Exogenous damage: generated as a result of exposure to extracellular agents AP (apurinic or apyrimidinic) or abasic site: type of damage where base has been lost, but sugar-phosphate backbone remains intact Cyclobutane pyrimidine dimer (CPD): major adduct following UV irradiation, occurring at adjacent pyrimidine nucleotides in the same strand thymine dimer: most prevalent CPD, occurring at adjacent thymines Single strand break: discontinuity in sugar-phosphate backbone of single DNA strand Double strand break: discontinuity in both strands at an individual location CAUSES OF DNA DAMAGE Alteration by chemical or physical agents Endogenous ROS and alkylation Exogenous agents Chemicals (mutagens, carcinogens) Tobacco and tobacco smoke constituents ( Lung and oral cavity ) Dietary components or contaminants ( GI tract and liver )...
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This note was uploaded on 04/24/2010 for the course IBS 602 taught by Professor Staff during the Spring '08 term at Kentucky.

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Orren IBS602-012710 - IBS602 Lectures #6 and 7 DNA Damage...

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