308 Lecture 13

308 Lecture 13 - 2) Spontaneous changes: C deamination U...

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2) 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-N 1 -nitro-N- nitrosoguanidine (known mutagens) • alkyl groups (mostly methyl) added to DNA e.g., methylation of O on C6 of guanine → O 6 -methylguanine reactive oxygen species : (H 2 O 2 , O 2 - , OH · ) generated by ionizing radiation and chemical agents • “ oxoG adduct” – guanine oxidized to 7,8-dihydro-8-oxoguanine – marker for oxidative stress 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 3) External factors (examples):
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ionizing radiation (X rays, gamma rays) : double strand breaks 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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Nature Reviews Cancer 3 ; 155-168 (2003); doi:10.1038/nrc1011 ATM AND RELATED PROTEIN KINASES: SAFEGUARDING GENOME INTEGRITY 3 1 2
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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 are necessary to correct errors arising during replication and to repair DNA damage caused by intrinsic and extrinsic agents DNA is repaired by both constitutive and damage- inducible enzyme systems {transposon insertion also causes mutation. ..that’s a different story. ..}
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1. Proof-reading or editing by DNA polymerase 2. Mismatch repair 3. Direct reversal of damage 4. Base excision repair 5. Nucleotide excision repair 6. Recombination repair 7. Error-prone repairs a) nonhomologous end joining and b) SOS translesion repair Repair mechanisms are redundant Repair DSBs Excision repairs http://sciencepark.mdanderson.org/labs/wood/DNA_Repair_Genes.html#DR
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Mismatch repair
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3’-5’ exonuclease activity of DNA polymerase(s) removes wrongly incorporated bases → improves fidelity but mismatches still occur
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308 Lecture 13 - 2) Spontaneous changes: C deamination U...

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