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Luo_Lecture7 Includes Summary

Luo_Lecture7 Includes Summary

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Michael M. Cox • Jennifer A.

Doudna • Michael O’Donnell

Molecular Biology
Principles and Practice

DNA Mutation and Repair

Copyright © 2012 by W. H. Freeman and Company

no functional impact 2 .s.evolution (rare) silent mutation .Lesion v.result in amino acid change that makes protein non-functional good . mutation Lesion: site of DNA damage Mutation: permanent base change bad .

Sources of DNA damage • Endogenous damages: internal agents from normal metabolic byproducts – Reactive oxygen species • Exogenous damages: external agents – – – – – – UV radiation from the sun X-rays and gamma rays Hydrolysis or thermal disruption Plant toxins Man-made mutagenic chemicals Viruses 3 .

UV-induced DNA damages 4 .

UV light • UV-A: 320-400 nm – majority of UV light reaching earth – does little DNA damage • UV-B: 295-320 nm – ~10% of UV light reaching earth – responsible for most of DNA damage in skin • UV-C: 100-295 nm – includes wavelength of maximum DNA absorbance (260 nm) – little reaches earth's surface due to ozone layer 5 .

Two pathways for UV-induced DNA damage • both involve dimer formation between adjacent pyrimidine rings on same strand • cyclobutane pyrimidine dimer (CPD) – accounts for 75% of UV induced damage • (6-4) photoproducts 6 .

. ASM Press. DNA Repair and Mutagenesis. et al. 2005.UV-induced cyclobutane pyrimidine dimer formation thymine-thymine dimers are most common cytosine-thymine and cytosine-cytosine dimers also form at slower rates Adapted from Friedberg. C. E. 7 . 2/3.

2005. 8 . DNA Repair and Mutagenesis.. et al.UV-induced (6-4) photoproduct formation Adapted from Friedberg. C. E. 2/3. ASM Press.

Natl. Proc. USA 99 (2002): 1596515970. Photo courtesy of ChulHee Kang.Cyclobutane pyrimidine dimers produce a kink in DNA Reproduced from Park. USA.. 9 . Copyright 2002.. Washington State University. et al. Sci. National Academy of Sciences. H. Acad.

Other DNA damages 10 .

[doi: 10. April 2001. P. and bonds linking exocyclic amine groups to bases are susceptible Adapted from Doetsch. John Wiley & Sons. 11 .els. N-glycosylic bonds.0000557]. Ltd..1038/npg.DNA has three types of bonds susceptible to hydrolytic cleavage phosphodiester bonds. W. Encyclopedia of Life Sciences.

AP site formation by N-glycosyl bond cleavage 12 .

Water-mediated deamination 13 .

Transition and transversion mutations caused by deamination Transition Transversion 14 .

DNA damage by hydroxyl radical 15 .

8-oxoguanine base pairs with C or A 16 .

ethyl. or larger alkyl groups to DNA • alkylation takes place at: – nitrogen and oxygen atoms external to the base ring systems – nitrogen atoms in the base ring systems except those linked to deoxyribose – non-bridging oxygen atoms in phosphate groups 17 .Alkylating agents damage DNA • transfer methyl.

Methylation results in mutation of GC pair to AT 18 .

chemicals. this will lead us to an opening of the ribose ring! -Water also cleaves the exocylic amine (the amine groups on the bases). WHAT ARE THEY 1)phosphodiester bonds 2)N-glycosylic bonds 3)exocyclic amine groups to bases -When DOES AN AP SITE FORM? When the N-glycosylic bond in cleaved. • • Mutations: Permanent base changes Sources of DNA damage: Endogenous (reactive o2 species) or exogenous (external agents: UV rays. X-RAYS. plant toxins. viruses) • UV: two pathways for UV-induced DNA damage both involve dimer formation btwn adjacent pyrimidine rings on same strand cyclobutane pyrimidine dimer (CPD) (6-4 photoproducts) --cyclobutane pyrimidine dimer produces a kink in DNA Other DNA damages DNA has three types of bonds susceptible to hydrolytic cleavage. N in base ring system except those linked to deoxyribose.Summary What I learned in this lecture…. -8-OXOGUANINE base pairs with C or A (GAC) GAGA AND CHRISTINE -Alkylating agents damage DNA! Where does alkylation take place? N and O external to ring system. WHAT are the RESULTS of this EXOCYCLIC AMINE BONDs BREAKING? Transition and transversion mutations! TRANSITION AND TRANSVERSION MUTATIONS ARE CAUSE BY DEAMINATION! -SIDE BAR: DNA DAMAGE can also occur by hydroxyl radical. hydrolysis or thermal disruption. gamma rays. non-bridging oxygen atoms in phosphate groups -METHYLATION RESULTS IN MUTATION FROM GC pair to AT! 19 . Ex: guanine 8-oxoguanine.

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