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PCL477H1-Lecture 5a to post - Lecture 5 overview (DSB

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Lecture 5 overview 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 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 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. Naturally occurring DNA transactions Te lo m e re s  – c hro m o s o m e  te rm inals   DNA re arrang e m e nts  in the  im m une  s ys te m   Exc hang e  o f g e ne tic  info rm atio n be twe e n ho m o lo g o us  c hro m o s o m e s 2. DNA backbone damage by radiation or chemicals alkylatio n o f pho s phate s o xidative  dam ag e  to  s ug ars   3. DNA damage that results in compromised or failed replication of DNA or segregation of DNA e .g . S talling  and c o llaps e  o f re plic atio n fo rks  – s ing le - and do uble -s trand  bre aks  induc e d whe n DNA re plic atio n fo rk e nc o unte rs  a dam ag e d te m plate / s ing le -s trande d bre ak in the  te m plate e .g . s e g re g atio n o f daug hte r c hro m o s o m e s  during  anaphas e  m ay re s ult in  DS Bs  due  to  m e c hanic al s he aring  o f c ro s s -linke d DNA
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DNA strand breaks caused by antineoplastic drugs and xenobiotics Alkylation of phosphates groups in DNA backbone: -any alkylating  ag e nt that c an re ac t with DNA bas e  has  po te ntial fo r c re ating   adduc t with pho s phate  g ro up Oxidative damage to DNA sugars: -abo ut 20%  o f hydro xyl radic als  that re ac t with DNA attac k the  s ug ars  in the   bac kbo ne e .g . 1-G y do s e  o f io nizing  radiatio n c an re s ult in 600 to  1000 s ing le -s trand bre aks   and 16 to  40 do uble -s trand bre aks
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