DNA Damage & Repair & Their Role in Carcinogenesis b The DNA sequence can be changed as the result of copying errors introduced by DNA polymerases during replication and by environmental agents, such as mutagenic chemicals and types of radiation. b If these changes are left uncorrected both growing and nongrowing somatic cells might accumulate so many mutations that they could no longer function.
DNA Damage By Carcinogenesis b The actual relevance of DNA damage and repair became evident when it was discovered that all agents that cause cancer also cause a change in the DNA sequence and are considered mutagens. b All the effects of these chemicals on tumor production can be accounted for by the DNA damage that they cause and by the errors introduced into DNA during the cells’ attempt to repair the damage.
How Carcinogens React with DNA b There are two categories of carcinogens depending on how they react with DNA. b 1. Direct-acting carcinogens, - which there are only a few. b 2. Indirect-acting carcinogens - are generally unreactive, water-insoluble compounds.
Direct-acting carcinogens b These carcinogens are reactive electrophiles, (which are compounds that seek out and react with negatively charged centers in other compounds). b These electrophiles react with nitrogen and oxygen atoms in DNA and then modify certain nucleotides and distort the normal pattern of base pairing. b If not corrected an incorrect nucleotide would be incorporated during replication and cause a mutation to occur.
Indirect-acting carcinogens b These carcinogens are generally unreactive, water-insoluble compounds. b They can act as potent cancer inducers only after conversion to ultimate carcinogens by the introduction of electrophilic centers. b The activation of such carcinogens are carried out by enzymes that are normal body constituents.
Activation of indirect-acting carcinogens in animals b This is often carried out by liver enzymes that normally function to detoxify noxious chemicals. b These compounds are usually so fat-soluble that they continually accumulate fat cells and lipid membranes that can’t be excreted from the body. b The detoxification system works by converting these compounds to water-soluble derivatives that can be excreted from the body.
DNA Damage Can Be Repaired b 1. Proofreading by DNA polymerases - They correct miscopied bases during replication. b However, cells have evolved mechanisms for repairing DNA damaged by chemicals or radiation.
Theory and Repair b Complex organisms with large genomes and long generation times contain many cells that divide very slowly or not at all. b So in theory, a carcinogen could act by binding to DNA and causing a change in the sequence that is maintained during DNA replication. b In order to prove this theory DNA-repair mechanisms have been studied in E. coli, using a combination of genetic and biochemical approaches.
Enzymatic Repair Mechanisms b 1. Mismatch Repair - which occurs immediately after DNA synthesis. It uses the parental strand as a template to correct an incorrect nucleotide incorporated into the newly synthesized strand. b 2. Excision Repair - is the removal of a damaged region by specialized nuclease systems and then DNA synthesis fills the gap.
Mechanisms Continued... b 3. End-Joining Process - Is the repair of double-strand DNA breaks in multicellular organisms.