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IUB BIOL-L 211 - Chemical and Environmental Mutagens and Cellular Damage Mechanisms

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BIOL-L211 Lecture 13 Outline of Last Lecture I. ArticleII. Proofreading and ErrorsIII. Mismatch Repair SystemOutline of Current Lecture I. MutagensII. Base Excision RepairIII. Nucleotide Excision RepairIV. Error Prone PolymeraseV. DNA PhotolyaseVI. MethyltransferaseCurrent LectureChemical and Environmental Mutagens and Cellular Damage MechanismsI. Mutagens: damage DNAA. Two Types:1. Chemical (ex: laboratory/industrial settings)2. EnvironmentalB. Examples1. UV radiation2. X-raysC. Effect on DNA1. Bases chemically altered- yields incorrect base pairinga. Water can cause deamination of cytosine, which yields uracil (which is not even supposed to be in DNA)These notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.b. Oxidized guanine pairs with adenine instead of cytosine 2. Formation of dimers (ex: thymine dimer)3. Next lecture will cover: double-stranded breaksII. Base Excision Repair: method of removing and replacing damaged bases (first method of control)A. Process:1. A glycosylase enzyme recognizes a damaged base where it shouldn't be (ex: uracil instead of cytosine)a. Note: glycosylases are specific2. Glycosidic bond is broken, removing the damaged basea. Damaged base is flipped out and away from double helix (so it becomes accessible); mechanism not understood completely, but glycosylase is likely responsible for the adjustment3. Either apyrimidinic or apurinic (AP site) is formeda. This site is a phosphate and a sugar4. Recall exonucleases and endonucleases; they find the AP site and make single stranded breaks5. The base is replaced by DNA polymerase6. Repair is completed by DNA ligase, which makes the phosphodiester bondB. Backup: Fail-safe glycosylases: find errant bases that were missed by base excision repair1. Fail-safe glycosylase finds where oxidized guanine has paired with adenine2. Cuts out adenine from new strand3. Inserts a cytosine in the proper location4. Gives cell another chance to remove the damaged guanine the next time aroundIII. Nucleotide Excision Repair: method of removing thymine dimersA. Problem:1. Fusion of two thymines caused by UV radiation (ex: sunburn)2. Prevents base pairing3. DNA polymerase has to stop during replicationB. Solution (mechanism in E. Coli per usual)1. UvrA and UvrB tetramer complex scans DNA, finding distortions (as opposed to specifically erred sequences)a. Called Uvr because the errors are caused by UV light2. UvrA is no longer necessary, so it leaves3. UvrB bubbles around the distortion, creating ssDNA that permits proteins to access the thymine dimers4. UvrC (looks like pair of headphones) makes single stranded nicks on either side of the distortion by UvrB5.UvrD helicase unwinds the single-strand fragment, which causes it to float away6. DNA polymerase and ligase fill in and close the gap (per usual)C. Backup1. If nucleotide excision repair fails, RNA polymerase will stall during transcription at the distortion site2. Nucleotide excision repair proteins will be recruitedIV. Error Prone Polymerases: When even base excision repair and nucleotide excision repair failA. DNA polymerase stalls encountering thymine dimers during replicationB. Solution: DNA polymerase replaced by error-prone polymerase for a stretchC. Problem: Error-prone polymerase is just as error-prone as it sounds (mutations likely)D. Advantage: Chromosome is replicated; lesion remains and repair pathways can come back and fix it (later repair pathways)V. DNA photolyase: reverses formation of thymine dimersA. Physically separates the two thymine residuesB. Necessary because thymine dimers form at high frequencyVI. Methyltransferase: enzyme that removes methyl groupsA. Methylated guanine acts like adenine (inserting an incorrect thymine in the resulting strand)B. Problem: Methyl group is really small and hard to recognize by repair systemsC. Solution:


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