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Lecture15_repair2012

Lecture15_repair2012 - 1 2 Experience the universal Mother...

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3 “Experience, the universal Mother of Sciences” Miguel Cervantes, Don Quixote
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Biochemistry 441 Lecture 15 Ted Young February 15, 2012 Topic for today: DNA repair
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Short youtube videos of DNA repair: http://www.youtube.com/watch?v=xj32VEkJ5IY&NR=1 http://www.youtube.com/watch?v=HYS6EKnQcv0&NR=1 http://www.youtube.com/watch?v=xS6bJMcOrAk&NR=1 http://www.youtube.com/watch?v=bgUH9NfO2QM&NR=1 nucleotide excision repair. http://www.youtube.com/watch?v=g4khROaOO6c&NR=1 Base excision repair.
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DNA repair rate is an important determinant of cell pathology
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7 Why repair DNA? 1. Errors in DNA replication 2. Endogenous DNA damage and mutagens 3. Environmental insults to DNA Unrepaired damage can lead to: -mistakes in RNA/protein synthesis -inherited as a genetic alteration-a mutation -apoptosis/cell death -senescence -cancer UV h ν OH . H + TT 8-oxoG depur- ination P/P Replication error All of these events are rare, but the number of bp in each nucleus is very large so the total frequency is significant. dUTP C U deamination
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8 Example of the product of a very small and a very large number yielding a significant effect Number of bp in the nucleus of a human cell=~6X10e9. Example #1: Rate of breakage of purine glycosidic bonds in neutral solution predicts =~10e4 depurinations/day/cell. X10e13 cells/human = 10e17 depurinations/day/organism! Example #2: UV in sunlight causes ~50 thymine dimers/sec/cell . If these are not repaired, it would lead to massive errors in the synthesis of proteins. Mutations in the germ line would be transmitted to offspring, possibly leading to genetic disease.
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9 Consequences of mutations (cont) Accumulation of mutations: -cancer (Loeb’s hypothesis): cancer is a genetic “disease” caused by an elevated mutation rate-as by an error-prone polymerase or faulty repair machinery. “Two-hit” model. Somatic versus germ line mutations. -aging (error catastrophe hypothesis); failure of normal cell death (apoptosis) due to accumulation of mutations in genes responsible for the normal operation of these processes. Single mutations and genetic disease-how many genes, when inactivated, would cause a “disease”?
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