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Lecture 7

Lecture 7.pdf

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Queen's University
BIOL 205

Mutations Due to Trinucleotide Repeats located in non-coding regions Fragile site on Fragile X chromosome -a CGG repeat expansion Leads to mental retardation Fragile X associated with autism Trinucleotide repeats in the FMR-1 gene (Fragile X Mental retardation gene) hinder transcription May lead to hypermethylation of DNA- shuts Down transcription. Slipped mispairing causes repeat expansion Figure 15-13 Molecular basis of Induced Mutations Mechanisms of mutagenesis • Incorporation of base analogs • Specific mispairing • Intercalating agents • Base damage 1.Incorporation of Base analogs - 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 Br replaces CH 3 -alters electrons in base Causes ii transition Ionizes Alternative pairings for 2-aminopurine Only mispairs when protonated Causes AT to GC transition Specific mispairing Alkylating agents –alter bases Ethylmethanesulfonate Nitrosoguanidine ethyl group added methyl group Alkylation-induced specific mispairings Figure 15-16 Intercalating agents- slips between bases – causes insertion or deletion of a single nucleotide pair BASE DAMAGE 2. Aflatoxin B1 forms a bulky addition product Figure 15-19 A deadly toxin produced by the fungus Aspergillus Low levels found in peanut butter! Breaks this bond! Results in base pair substitutions and/or replication blocks • 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 – Can cause • Base deletions Marie Sklodowska • Single nicks in DNA strands Curie Nobel Prize in • Cross-linking Physics 1903 • Chromosomal breaks Nobel Prize in Chemistry 1911 • Nonionizing radiation – Includes UV light – Has less energy – Cannot penetrate deeply into biological molecules – Causes the formation of cross- linked thymine dimers and 6-4 photoproducts – They may cause mutations when that DNA strand is replicated T esting Methods Can Determine If an Agent Is a Mutagen • Many different kinds of tests have been used to evaluate mutagenicity – One commonly used test is the Ames test • Developed by Bruce Ames • The test uses a strain of Salmonella typhimurium that cannot synthesize the amino acid histidine – It has a point mutation in a gene involved in histidine biosynthesis • A second mutation (i.e., a reversion) may occur restoring the ability to synthesize histidine • occurses test monitors the rate at which this second mutation The Ames test reveals mutagenic compounds Some salmonella strainFigure 15-20 revert through base-pair substitution Others require frameshift DNA REP AIR • Since most mutations are deleterious, DNA repair systems are vital to the survival of all organisms – Living cells contain several DNA repair systems that can fix different type of DNA alterations • In most cases, DNA repair is a multi-step process – 1. An irregularity in DNA structure is detected – 2. The abnormal DNA is removed – 3. Normal DNA is synthesized Proofreading function of DNA polymerase I and III first defense! 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 DNA to its original condition – O -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! A photodimer may be reversed by direct repair Figure 15-22 Should be CPD Photolyase i.e. cyclobutane pyrimidine dimer Minor base damage is detected and repaired by base-excision repair Numerous exist Repair system Generates apurinic or is homology apyrimidimic site dependent Cut made upstream of AP site Deoxyribophosphodiesterase Xeroderma Cockayne Pigmentosum Syndrome Skin cancer UV light sensitivity Developmental Disorder -dwarfism -deafness Both conditions due to -mentally impaired Defects in nucleotide excision -premature aging repair Nucleotide excision repair normally activated When replication fork stalls or is blocked Block can also stall Transcription DNA RNA -Activates nucleotide Excision repair Two pathways for nucleotide-excision repair Repairs transcribed
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