Various ways in which DNA damage leads to mutations in proteins Insertion

Mutation Genetic Mutations leading to food production Canola Cauliflower

Carcinogens –Carcinogens – agent that inducing mutation of DNA leading to cancer –Procarcinogens – are not carcinogens, but can be activated by metabolic processes Ames test His - strain of bacteria Salmonea tyrphimurium His - can not synthesize His Mutagenesis indicates reversion of strain to His+ Cells of S. tyrphimurium is spread on culture plate lacking his in the presence of tested mutagent, growing cells indicated reversion to His+ strain.

UV, short wave length (254nm) –Covalently link adjacent pyrimidines along one side – cis-syn-cyclobutane pyrimidines dimers –Thymine or cytosine dimers –Formation of dimer distorts base pairing structure=> effect replication and transcription

Pyridimine-pyrimidine(6-C4) photoproducts 이량체의 25% 3 시간 후 자동제거

Psoralen, intercalating agent photosensitizer w/ 장파장 UV

DNA damage oxidative deamination: spontaneous reaction at 37 o C GuanineXantine

Reaction with alkylation agents -Addition of methyl group to bases - S-adenosylmethionine - some agents used in chemotherapy

Cytosine Thymine Alkylation agent Alkylation of guanine O 6 -methylguanine

BenzopyreneBenzopyrene Dihydrodiol epoxide

Reaction with ROS ; –Number of mutations increase with age guanine Depurination – cleavage of glycosyl bond results into removal of base - abasic sites, apurinic sites

DNA glycosylases remove altered bases Deamination of cytosine, particularly 5-methyl cytosine leaves uracil (thymine if 5methyl cytosine) in the DNA. Uracil would pair as thymine during replication and thus cause a mutation. Uracil-N-glycosylase removes uracil from DNA. An endonuclease then cleaves the backbone at that site, creating a substrate for NER

Nucleotide excision repair Variety of damages, includes pyrimidine dimers, chemotherapic agents as cis platine Repair mechanism involves removal of several nucleotides E. coli: UvrABC endonuclease complex UvrA – recognize helix distortion UvrB – separation of DNA strands (helicase activity UvrC – catalyses dual cleavage UvrD – exonuclease activity removes oligonucleotide Pol I fills the gap DNA ligase – couple the nick

Mismatch repair corrects the unmethylated strand What happens if the “old” strand needs repair? eg 5-methyl cytosine>deamination to 5-methyl uracil (=thymine!). In E. coli a small fraction of C is 5-methylated and these are “hot-spots” for spontaneous mutation. This implies that 5-methyl cytosine is frequently either not repaired or is mistakenly repaired on the “wrong” strand. Mis-paired bases

색소건피증 Xeroderma pigmentosum 햇볕에 극도로 민감 PD 절제회복의 결함, 피부암으로 발전

Cockayne syndrome 전사가 빠른 유전자의 DNA 상해회복의 결손 난장이, 조로