orren 3 IBS602-020110

orren 3 IBS602-020110 - IBS602 Lecture #8, 2/2/09 DNA...

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IBS602 Lecture #8, 2/2/09 DNA Recombination and Transposition Chapters 11 and 12 David Orren Graduate Center for Toxicology 356 HSRB email: dkorre2@uky.edu Phone: 3-3612
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DNA Double Strand Breaks Extremely deleterious one unrepaired double strand break/cell can be lethal often have non-ligatable ends only 3’-OH and 5’-PO 4 ends are appropriate for synthesis and ligation Strand break generating agents Ionizing radiation (X-rays, gamma rays) Oxidative treatments (H 2 O 2 ) Chemotherapeutic agents (bleomycin, neocarzinostatin, topoisomerase inhibitors) Special cases of programmed/targeted double strand break generation mating type switching in yeast immunoglobulin gene rearrangements Repaired by two pathways Non-homologous end-joining (NHEJ) simply splices together broken ends loss of sequence (deletion) at the site of the break most utilized in G 1 and differentiated cells required for V(D)J recombination process of immunoglobulin diversity Individuals with defects in NHEJ factors have profound immunodeficiency Homologous recombination uses sister chromatid or homologous chromosome (diploid) more often used in S and G 2 phases
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Pathways for repair of double-strand breaks G1 S and G2 sister chromatid/
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In humans, NHEJ appears to predominantly act in G1, while HR acts during S and G2 phases This choice may depend on whether the ends of the break are processed by CtIP nuclease (or not) to yield a 3’ overhang that is appropriate for filament formation and strand invasion CtIP is upregulated during S and G2 Choice of double-strand break repair pathway Takeda et al. (2007). Mol. Cell 28:351
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Mechanism of Non-homologous End Joining Hefferin and Tomkinson (2005). DNA Repair 4:639
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Homologous Recombination (HR) Meiosis and Genetic diversity Exchanges segments of homologous chromosomes to rearrange chromosomes and genes If this did not occur, all traits proscribed by genes on a particular chromosome would remain linked Immune system function Immunoglobulin gene rearrangement Double-strand break repair Resolution of replication blockage and replication restart (unconventional HR pathways) Tool for genetic manipulation Defects in genes involved in HR pathways may increase cancer susceptibility (for example, BRCA genes and breast cancer)
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Homologous Recombination: How does it work? In all cases, “ homologous recombination " involves Watson-Crick base- pairing between strands that have not been previously paired together— i.e., creation of “new” DNA duplexes via means other than DNA synthesis. "Homologous" originally referred to sequences that shared an evolutionary relationship with each other (e.g., homologous chromosomes, maternal and paternal versions of a particular chromosome), but now is used to mean any two sequences that share a large degree of sequence identity with each other. The term “homeologous” is sometimes used for sequences that share significant
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orren 3 IBS602-020110 - IBS602 Lecture #8, 2/2/09 DNA...

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