Topic 21 - DNA repair.docx

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Biochemistry 2280A
Chris Brandl

Topic 21 Topic 21: DNA repair Damage: any unintended physical or chemical change in DNA or its sequence. DNA molecules are huge and prone to damage. Cells have developed mechanisms for repairing DNA damage Main types of DNA damage 1. Copying Mistakes  Mistakes occur in DNA replication at rate of 1 per 10^7 nt in humans  Result is one or more mismatched bp, leading to change in DNA sequence  mutation in one of daughter double helices after replication  Insertion or deletion of one or more bases potentially causing a shift in reading frame  can lead to nonsense mutations Polymerase sees A, assumes it is supposed to be T - make mistake in round 1  ¼ round 2 will have mutation - if not caught at round 1, cannot be fixed because found 2 doesn’t notice mistake 2. Deamination:  Amine group of nitrogenous base, usually cytosine, is changed to carbonyl  Occurs spontaneously and may lead to mutation  Result: Substitution U for C Mistake is recognized even in round 2 because U is not found in DNA Assumes other strand is correct, so A is used as template As a result, C  U  T 3. Depurination 1 Topic 21  Acid promotes loss of entire A of G base, resulting in abasic site  spontaneous  Sugar phosphate backbone remains intact  Result: Abasic sites block replication by normal replicative DNA polymerase (can be overcome by error-prone translesion DNA polymerase)  Bad for polymerase to get stuck because it is on a time clock and if it doesn’t finish its job before cell wants to divide, one daughter cell will be short changed DNA  often leads to cell death  When DNA polymerase stalls, one of several translesion DNA polymerases is recruited to site  Translesion DNA polymerases able to synthesize DNA past site of damage, but because template has no base, are likely to skip that position or introduce mutations in newly synthesized strand  After translesion polymerase has synthesized DNA past site of damage, normal replicative DNA polymerase resumes DNA synthesis Loose G  A-basic site (site without base) Polymerase tries to replicate by stalls when comes to site with no base so it dissociates Translesion DNA comes in and puts in any base because it doesn’t know what it was  chance it gets it right (normally C or A) Polymerase comes back in after a few bases and continues Second round: use bottom strand as template, adds A. All progeny of cell will have mutation 4. Pryimidine dimers  UV light causes formation of cylcobutane ring between adjacent pryimidines (normally TT)  Result: blocks DNA replication (can be overcome by translesion polymerase)  Translesion DNA polymerases required to replicate DNA past pyrimidine dimers, but more error-prone that normal replicative DNA polymerases, increasing risk of mutation 5. other base modifications  Ionizing radiation (X rays, gamma rays) cause modifications at all 4 bases  Some chemical mutagens react with DNA bases leading to sequence changes 2 Topic 21 o Mutagen superoxide radical O2 – first intermediate formed during reduction of oxygen to water by cytochrome oxidase  Result: chemical changes in bases, resulting in mutations or breakage of sugar phosphate backbone  strands can float away DNA Repair Mechanisms - single alteration could interfere with replication, may cause cell death, damage DNA leading to mutations 1. Proofreading during DNA replication 2. Mismatch Repair:
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