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Spring 09 lecture 12

Spring 09 lecture 12 - DNA repair Learning objectives to...

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DNA repair : Learning objectives: to define the causes of DNA damage to examine the mechanisms for DNA repair
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Genome of bacteria and yeast: several % of coding capacity is occupied by genes coding for proteins involved in DNA repair DNA structure great for repair : if one strand is damaged, the complementary strand serves as template for repair (back-up copy of genetic material) Sources of mutations: Replication errors: mistakes made during replication that were not detected and corrected by DNAP I/III proofreading mechanisms Spontaneous changes in DNA : -around 5000 depurinations / human cell / day -around 100 spontaneous deaminations of C into U / human cell / day External factors (radiation, change in temperature, mutagens etc.) Almost all mistakes efficiently repaired
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Replication error: A inserted instead of C : (Lewin, 2006. Fig. 20.4) A T C G is not corrected result in one daughter chromosome is A:T in place of C:G (mutation) if mismatch
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Spontaneous changes : C deamination → U occurs spontaneously under normal physiological conditions others incl A → hypoxanthine (which pairs with C, not T) depurination: spontaneous hydrolysis of N-glycosyl linkage → abasic site in DNA
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alkylating chemicals : e.g., nitrosamines, N-methyl-N1-nitro-N- nitrosoguanidine (known mutagens) alkyl groups added to DNA e.g., methylation of O on C6 of guanine → O6-methylguanine reactive oxygen species : (H2O2, O2-, OH · ) generated by ionizing radiation , chemical agents oxoG adduct” – guanine oxidized to 7,8-dihydro-8-oxoguanine highly mutagenic – base pairs with A and C nonionizing radiation (UV light) : 260 nm UV strongly absorbed by bases photochemical fusion of two pyrimidines that occupy adjacent positions in same DNA strand thymine dimer – cyclobutane ring generated by linking C5, C4 of adjacent thymines thymine-cytosine adduct – C6 of thymine links to C4 of cytosine External factors
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ionizing radiation (X rays, gamma rays) : double strand breaks e.g., direct ionization of deoxyribose base analogues : e.g., 5-bromouracil = thymine analogue that mispairs with guanine intercalating agents : e.g., acridine, ethidium bromide flat, polycyclic molecules that insert between stacked DNA bases → may cause deletion or addition of one–few base pairs when polymerase subsequently skips or adds one or more nucleotides
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Failure of DNA to get repaired prior to next round of replication will lead to permanent change in DNA - MUTATION - which could be detrimental for the cell if the mutation occurred in a germ cell or germ cell precursor - disease predisposition may be(come) hereditary If the mutation occurred in a somatic cell - non-hereditary disease (e.g. cancer) DNA repair mechanisms - necessary preservation of the (fidelity of) information DNA is repaired during and after replication Multiple repair mechanisms
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