Lecture 7 Flashcards
Where do somatic mutations occur? Are they heritable?
Non-germline tissues; non-heritable
What are the three types of mutations?
Single base substitution, insertion, deletion
Where do germline mutations occur? Are they heritable?
Egg or sperm; are heritable
What mutation causes cancer family syndrome?
Germline mutations
Do most cancers arise from somatic or germline mutations?
Somatic
Are acquired mutations found in some or all cells of the body?
Some
What are some internal factors that can damage DNA?
Depurination, deamination, reactive oxygen species
When and where does depurination occur?
Spontaneously; in aqueous solution
What does depurination result in?
An abasic site (loss of nucleotide base)
When and where does deamination occur?
Spontaneously and under neutral pH
What does deamination result in?
Changes in DNA sequence (mutation), unless repaired
How do reactive oxygen species damage DNA?
Oxidation of nucleotide bases
What three enzymes eliminate reactive oxygen species?
Superoxide dismutase, glutathione peroxidase, and catalase
What reaction does superoxide dismutase catalyze?
Superoxide (O2-) –> hydrogen peroxide (H2O2)
What reaction does glutathione peroxidase + catalase catalyze?
Hydrogen peroxide (H2O2) –> hydroxyl radical (OH-) –> water
What is carcinogenesis?
Process by which normal cells are transformed into cancer cells
What kind of DNA damage does UV radiation cause?
Covalent cross links between adjacent thymines –> thymine dimers
What was the first discovered chemical carcinogen?
Benzo[a]pyrene (BP)
Where is benzo[a]pyrene found, and what does it cause?
Found in chimney soot, tar, tobacco smoke, combustion products; causes Chimney sweep’s cancer
What is the structure of benzo[a]pyrene?
Polycyclic aromatic hydrocarbon (PAH)
What are the three major categories of carcinogens?
Alkylating agents, aralkylating agents, and arylhydroxyamines
What do the three major classes of carcinogens have in common?
Compose 95% of all carcinogens, are electrophiles which will react with amines or double bonded oxygens, and they can covalently bind DNA
What is a DNA adduct?
Piece of DNA covalently bonded to a carcinogen
What are direct carcinogens?
Carcinogens that can readily and directly bind DNA
What are indirect carcinogens?
Compounds that are not carcinogenic themselves, but can be turned into one in the body
What are two examples of indirect carcinogens?
Benzopyrene and aflatoxin
What is biotransformation?
Process by which the body modifies chemical toxins to make them more water soluble and thus increase the rate of its secretion
Which enzymes are primarily responsible for biotransformation?
Cytochrome P450 enzymes
Alkylation of DNA forms what structure?
A DNA adduct
What is the Ames test?
Test using bacteria to screen for carcinogens that cause mutation
How does tissue organization help prevent mutations?
Stem cells are located to the interior of the organ
Proofreading of the genome is accomplished by what activity?
3’-5’ exonuclease activity
What two steps ensure replicative fidelity of the genome?
- Selection of the correct nucleotide to be incorporated 2. Proofreading activity of polymerase
What are melanosomes?
Granules (vesicles) containing melanin
What does melanin protect against?
UV radiation
What is the function of the glutathione S-transferase (GST) family of enzymes?
Catalyze the conjugation of glutathione to chemical compounds to help in detoxification
What is glutathione a tripeptide of?
Glutamic acid, cysteine, and glycine
What gives glutathione its detox ability?
Sulfhydryl group of cysteine
What are the 3 phases of biotransformation?
- Modification 2. Conjugation 3. Excretion
What enzymes are responsible for biotransformation modification?
Cytochrome P450 class enzymes
What enzymes are responsible biotransformation conjugation?
Glutathione S-transferase
How can cells circumvent senescence (in culture)?
Expression of SV40 large T (LT) antigen
What effect does SV40 LT antigen have in the cell?
Sequesters and inactivated tumor suppressor proteins pRB and p53
Mutations in this gene can cause abnormal senescence
BRCA1
Is inducing senescence alone enough to treat cancer cells?
No, cancer cells can circumvent senescence
