PCL477H1-Lecture 5a to post [Compatibility Mode]

PCL477H1-Lecture 5a to post [Compatibility Mode] - Lecture...

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Lecture 5 overview concept of DNA double-strand breaks (DSB) concept of DNA double strand breaks (DSB) strand breaks produced by clastogenic agents strand breaks produced by endogenous processes pathways of double-strand break repair pathways of double strand break repair pathways single-strand break repair how can we study strand break repair consequences of defective double-strand break repair
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DNA Strand break concept damage to DNA bases -potential to alter coding information in the genome mutagens : agents that - result in DNA base damage damage to the DNA d bl h li b kb double-helix backbone -fracture of the sugar- phosphate backbone clastogens: agents that result in DNA backbone damage
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Double-strand breaks How are they formed? (gimme a break) 1 N ll DN 1. Naturally occurring DNA transactions Telomeres – chromosome terminals DNA rearrangements in the immune system Exchange of genetic information between homologous chromosomes 2. DNA backbone damage by radiation or chemicals alkylation of phosphates oxidative damage to sugars 3 DNA d th t lt i i d f il d li ti f 3. DNA damage that results in compromised or failed replication of DNA or segregation of DNA e.g. Stalling and collapse of replication forks – single- and double-strand breaks induced when DNA replication fork encounters a damaged template/single stranded break in the template template/single-stranded break in the template e.g. segregation of daughter chromosomes during anaphase may result in DSBs due to mechanical shearing of cross-linked DNA
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DNA strand breaks caused by ti l ti d d bi ti antineoplastic drugs and xenobiotics Alkylation of phosphates groups in DNA backbone: -any alkylating agent that can react with DNA base has potential for creating adduct with phosphate group Oxidative damage to DNA sugars: -about 20% of hydroxyl radicals that react with DNA attack the sugars in the backbone e.g. 1-Gy dose of ionizing radiation can result in 600 to 1000 single-strand breaks d 16 40 d bl d b k and 16 to 40 double-strand breaks ROS capable of producing DNA single-strand breaks and when two of these
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