Duquette+photomed+lecture

Duquette+photomed+lecture - Cell Surgery II. Biophotonics...

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Unformatted text preview: Cell Surgery II. Biophotonics and DNA Repair Michelle Duquette, Ph.D. DNA Damage Different Types of DNA Damage Double strand break Single strand break Mono-adduct Interstrand cross-link Intrastrand cross-link UV photoproduct Sources of DNA Damage Endogenous Exogenous Image by Jiashan Wang Scientificrelevance.com Endogenous Sources of DNA Damage Reactive metabolic byproducts Oxidative damage (by free radicals) Bulky adducts Errors in replication and transcription à mismatch of bases, wrong base inserted What about DNA replication errors? DNA polymerases make an error once every 109 to 1011 bases In an average human lifetime there will be 1017 cell divisions Each cell must replicate 3.2 billion base pairs each cell division, that is a lot of opportunity for error! Exogenous Sources of DNA Damage UV-A (365 nm) UV-B (260nm) Pyrimidine dimers and free radicals DNA breaks DNA crosslinks, modified DNA bases, DNA breaks How much DNA damage is present in our genome at any given time? Due to oxidative damage alone How much DNA damage is present in our genome at any given time? Estimates range from 200 to 450,000 sites of damage! Per Cell Reviewed in Bont and Larabeke, 2004 How many per person? Lucky for us our cells have evolved to efficiently repair DNA damage! But what happens if the DNA damage load is SO high our cells cant repair it? Unrepaired DNA Damage Causes Cell Death Arends and Wylie, 1991 Cell Cycle Arrest If DNA repair is inaccurate you accumulate DNA mutations Accumulation of DNA Mutations Causes Aging Cancer Diverse phenotypes and Disease DNA repair proteins are important! Many repair proteins are essential Genetically engineered mice lacking certain single repair genes are not viable Syndrome resulting from mutation in single repair gene Werner syndrome- mutation in DNA helicase required for DNA repair Accelerated aging, early onset cancer Understanding DNA Repair is also Important for Developing Effective Chemotherapeutic Approaches Chemotherapy A subset of chemotherapeutic agents takes advantage of toxicity of DNA damaging agents to kill actively dividing cells DNA adducts DNA crosslinks (interstrand and intrastrand) Radiation- DNA breaks Problems Arise with Standard Chemotherapy Anti-tumor Chemotherapy (DNA damaging agents) Tumor Regression Arrest of cell growth (senescence) Cell death Negative side effects Surviving cells Drug resistance-increase in drug efflux-increase in DNA repair Increased mutation load Increased cancer risk How does understanding DNA repair processes help us develop better targeted chemotherapy? Lung Cancer Cisplatinin is a platinum based agent commonly used to...
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Duquette+photomed+lecture - Cell Surgery II. Biophotonics...

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