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 carcinog

ens, but can be activated by metabolic processes

Ames testHis- strain of bacteria Salmonea tyrphimuriumHis- can not synthesize HisMutagenesis 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 pyri

midines along one side– cis-syn-cyclobutane pyrimidi

nes dimers– Thymine or cytosine dimers– Formation of dimer distorts b

ase 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 37oC

N

NN

N

O

NH2

H

H

N

NN

N

O

O

H

H

Guanine Xantine

Reaction with alkylation agents

-Addition of methyl group to bases- S-adenosylmethionine

- some agents used in chemotherapy

N

N

NN

O

NH2

HH

N

N

NN

O

NH2

H

CH3

Cytosine

Thymine

Alkylation agent

Alkylation of guanine

O6-methylguanine

Benzopyrene Benzopyrene Dihydrodiol epoxide

• Reaction with ROS;– Number of mutations increase with age

N

NN

N

O

NH2

H

Hguanine

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 repairVariety 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 activityUvrC – catalyses dual cleavageUvrD – exonuclease activity removes oligonucleotidePol I fills the gapDNA 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 ofC is 5-methylated and these are “hot-spots” forspontaneous mutation. This implies that 5-methyl cytosine is frequently either not repaired or ismistakenly repaired on the “wrong” strand.

Mis-paired bases

색소건피증 Xeroderma pigmentosum

햇볕에 극도로 민감PD 절제회복의 결함 , 피부암으로 발전

Cockayne syndrome

전사가 빠른 유전자의 DNA 상해회복의 결손난장이 , 조로