Lecture21S10 - BIS101/Engebrecht Lecture21 Website for mutations http/www.justinbadal.com/mutations/index.html Mechanisms of Spontaneous

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BIS101/Engebrecht Lecture21 5/20/2010 Website for mutations: http://www.justinbadal.com/mutations/index.html Mechanisms of Spontaneous mutagenesis = naturally occurring 1) Transposition – insertional mutations caused by transposons (jumping genes, more on this next week). It turns out that half of all spontaneous mutations in Drosophila are due to transposon insertions. 2) Replication errors: A) caused by DNA polymerase slippage in homopolymeric runs (meaning stretches of the same nucleotide). We drew out how this happens on a piece of DNA. If the newly synthesized strand slips, then this would lead to an insertion of a nucleotide; if the template (old) strand slips, then this would lead to a deletion of a nucleotide. “Hotspots” of mutations usually occur in such stretches of DNA. Several human diseases are due to polymerase slippage at repeated triplets in the DNA (e.g., fragile X syndrome, Huntington’s disease). B) Replication errors - ~1/10 4 -1/10 5 bases of DNA undergo tautomeric shifts that change the base pairing potential leading to base substitution mutations. These shifts result in different isomers of the bases and thus different base pairing (Figure 14-6 in 8 th edition; Figure 15-10 in 9 th edition). Because of the frequencies of these shifts, there must be mechanisms to enhance replication fidelity (see below). C) Changes in the bases due to the cell’s own chemistry. Examples of these are depurinations, which cause an interruption of the glycosidic bond and deaminations of Cs and 5-methylC (Figure 14-18 in 8 th edition). In the case of Cs, such a deamination results in the production of uracil. Since this is not a normal base, it will be recognized and repaired by specific enzymes. However, 5- methylC is converted to thymine, a normal constituent of DNA, thus this will usually result in a transition mutation. Bases will also be altered by reactive oxygen generated from aerobic metabolism. How do cells repair all of this damage? Several mechanisms exist but we will first look specifically at damage caused during replication. I reminded you about the fidelity of DNA replication (a single misincorporated base in 10 10 nucleotides). This is due to a combination of factors: 1) Watson-Crick base pairing (base pairing will be correct 99% of the time) 2) DNA polymerase base selectivity and proofreading-remember the 3’ 5’ exonuclease activity that is activated when the wrong base is inserted and removes it (this reduces the error rate to 1/10 5 -1/10 6 bases) 3) Accessory proteins of DNA polymerase increase fidelity to 1/10 7 . 4) Post-replicative mismatch repair (MMR) This is a carried out by proteins that are conserved throughout evolution. In bacteria, they are referred to as MutS, MutL, and MutH. Mut stands for mutator, which is the phenotype of cells harboring mutations in any of these genes, they have an increased rate of mutations. We went over Handout23MMR . MMR requires that the mismatch is recognized, the newly synthesized strand is identified
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This note was uploaded on 07/02/2010 for the course BIS 101 taught by Professor Simonchan during the Spring '08 term at UC Davis.

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Lecture21S10 - BIS101/Engebrecht Lecture21 Website for mutations http/www.justinbadal.com/mutations/index.html Mechanisms of Spontaneous

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