9- Carcinogenesis/ DNA Damage & Repair

• mutations accumulate over time > ↑ cancer with age • cells accumulate genetic changes as tumor progression proceeds

Succession of Clonal Expansion - random mutations in a cell providing survival/ proliferation advantages are passed on to descendants

• chromosome translocation of tip of chromosome 9 with larger portion of chromosome 22 > in 95% of all CML (chronic myeloid leukemia)

• change in genotype that alters the nucleotide sequence of a DNA segment

• anything capable of causing cancer • does NOT mean that it will always cause cancer

Group 1- Carcinogenic to humans > ethanol Group 2A- Probably carcinogenic to humans > red meat Group 2B- Possibly carcinogenic to humans > gasoline Group 3- Not classifiable carcinogenicity in humans

• Epidemiological studies > humans exposed to agent • Experimental studies > lab animals treated with agent • Response to agent > evidence of mechanisms

• link between ability of chemical to mutate bacteria (salmonella) and ability to induce tumors in rodents > all mutagenic compounds likely to also be carcinogenic BUT NOT all carcinogenic compounds likely to also be mutagenic

• not all mutations have negative consequences (codon redundancy) • mutations can alter biochemical properties like polarity

• single base pair changes > substitutions/ insertions/ deletions Silent- 1 changed/ same AA > no effect (codon redundancy) Nonsense- STOP codon > no longer functional protein (truncated) Missense- Conservative > lose AA but not polarity Missense- Non-conservative > lose AA and polarity

• loss of function > inactivate tumor suppressors • gain of function > activate oncogenes • gain of novel function > neomorphic mutations

• breakage at replication fork • depurination/ depyrimidination • deamination • ROS

Purines- Adenine/ Guanine (2 ring bases) Pyrimidines- Thymine/ Cytosine/ Uracil (1 ring bases)

• during replication, DNA unwinds/ forms 2 single strands through the action of helicase/ replication fork • single-stranded DNA is vulnerable to break • altered bases cause DNA polymerase to stall as it recognizes abnormal base > puts strain on the strands • consequence = loss of DNA

Depurination > G-A - hydrogen in environment (H20) causes a spontaneous break between purine/ deoxyribose Depyrimidination > C-T - deletion of a bp causes a frameshift in sequence (read wrong) > frameshift mutation

Transition- purine > purine/ pyrimidine > pyrimidine Transversion- purine > pyrimidine/ pyrimidine > purine

Transition mutation

• react and form covalent bonds with bases of DNA > strand breaks/ change base pairing • consequence = transversion mutation

• ionizing radiation/ UV radiation • Aflatoxin (mould) > xenobiotic mutagen • Heterocyclic amines

• cause pyrimidine dimers (photoproducts) = covalently bonded/ adjacent pyrimidines • very stable/ remain for long periods of time > skin cancer • causes CC > TT substitution

• potent exogenous carcinogen • attacks guanine forming DNA adducts • causes G > T transversion mutation

• formed when meats cooked at high temps • processes oxidize rings/ anime groups from the rings • creates reactive compounds that form covalent bonds with DNA > bulky lesions > DNA breaks

• physical protection (skin) > melanin delivered to keratinocytes in epidermis/ form supranuclear caps/ cover keratinocytes from UV radiation • free radical scavengers (vitamin E/C) > donate electrons to turn ROS into H20 • detoxification > Glutathione S Transferase > links carcinogens to glutathione/ allows inactivation/ excretion

• Proofreading (DNA polymerase is a fast/ sloppy enzyme) • MMR (Mismatch Repair) > catch DNA polymerase overlooked mistakes