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BIOL 205
Ian D Chin- Sang

BIOL205:week 9, lecture 24 Mutations Due to Trinucleotide Repeats located in non-coding regions Trinucleotide repeats in the FMR-1 gene (Fragile X Mental retardation gene) hinder transcription Slipped mispairing causes repeat expansion **repeats don't need to happen in codin region: can happen in heterochromatin, promoter, etc. Ifexposed to light greater than 320nm:dangerous Space travel Molecular basis of Induced Mutations -cosmic rays:gamma and other type s ofradiation -have repair mechanisms BUTthey are dependent on Mechanisms of mutagenesis dose (point that mechanisms can no longer keep up) • incorporation of base analogs • specific mispairing • intercalating agents • base damage 1. Incorporation of Base analogs: can be incorporated and not recognized by repair mechanisms • chemicals that resemble normal nitrogen bases- get incorporated into DNA ◦ 5-bromouracil (5-BU) ◦ 2-aminopurine • alternative pairings for 5-bromouracil (5-BU)- an analog of thymine **5-BU more easily ionized Alternative pairings for 2-aminopurine → causes A-T to G-C transition Resembles adenine Specific mispairing – Alkylting agents → alter bases Alkylation-induced specific mispairings Usuallytransitions (transversions = energeticallyunfavourable and repaired quickly) Intercalating agents-slips between bases → causes insertion or deletion of a single nucleotide pair: frameshift (far more deleterious than transitions) flat, planar molecules BASE DAMAGE 2. Aflatoxin B1 forms a bulky addition product Physical mutagens • come into two main types 1. Ionizing radiation 2. Nonionizing radiation Ionizing radiation • includes X rays and gamma rays • has short wavelength and high energy • can penetrate deeply into biological molecules • creates chemically reactive molecules termed free radicals (ex: superoxides, O , 2xidizing agents) • can cause: ◦ base deletions ◦ single nicks in DNAstrands ▪ lead to double strand breaks ◦ cross-linking (ex: thymine dimers) ◦ chromosomal breaks ▪ worst possible thing: very difficult to put chromosome back together Nonionizing radiation • includes UV light, has less energy • cannot penetrate deeply into biological molecules • causes the formthion ofthross-linked thymine dimers (connecting 5 and 6 position in two thymine neighbouring molecules) and 6-4 (connecting 6 and 4 of neighbouring thymine) photoproducts • they may cause mutations when that DNAstrand is replicated Testing Methods Can Determine If anAgent Is a Mutagen • many different kinds of tests have been used to evaluate mutagenicity • one commonly used test is the Ames test ◦ developed by BruceAmes ◦ the test uses a strain of Salmonella typhimurium that cannot synthesize the amino acid histidine See figurestrain 1: has a point mutation in a gene involved in histidine biosynthesis below ▪ strain 2: require a frame mutation to synthesize histidine ▪ both unable to grow on minimal media without histidine ◦ a second mutation (i.e., a reversion) may occur restoring the ability to synthesize histidine ◦ theAmes test monitors the rate at which this second mutation occurs The Ames test reveals mutagenic compounds count colonies:see what reversion frequencyis no mutants:controlto see if creatingmutants just byadding liver enzymes DNAREPAIR • since most mutations are deleterious, DNArepair systems are vital to the survival of all organisms • living cells contain several DNArepair systems that can fix different type of DNAalterations • in most cases, DNArepair is a multi-step process 1. An irregularity in DNAstructure is detected 2. The abnormal DNAis removed 3. Normal DNAis synthesized • proofreading function of DNApolymerase I and III first defense! Base pair mismatch→ need to recognize whichis parent and which is daughter Damaged Bases Can Be Directly Repaired • in a few cases, the covalent modifications of nucleotides can be reversed by specific enzymes ◦ Photolyase can repair thymine dimers ▪ It splits the dimers restoring the DNAto its original condition ◦ O6-alkylguanine alkyltransferase repairs alkylated bases ▪ it transfers the methyl or ethyl group from the base to a cysteine side chain within the alkyltransferase protein • conveniently, this permanently inactivates alkyltransferase (itself)! A photodimer may be reversed by direct repair Enzyme recognizes thymine dimer but it is onlyactivated bylight! Minor base damage is detected and repaired by base-excision repair → Repair system is homology dep
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