WEEK 3: Carcinogenesis Flashcards
Define the following terms:
1. Mutation
2. Germ cell mutation
3. Somatic cell mutations
4. Give examples of cancers associated with each type of mutation.
- MUTATION
Permanent change in the DNA sequence of an organism.
Germ cell mutations are transmitted to the progeny inherited diseases.
- GERM CELL MUTATION:
A mutation that occurs in a germ cell (egg or sperm cell) and can be inherited by the offspring.
-Examples of cancers: breast, ovarian, colorectal cancer and retinoblastoma
- SOMATIC CELL MUTATION
Somatic cell mutations do not cause hereditary diseases Cancers some congenital malformations.
Somatic mutations are a change to a person’s DNA that occurs after conception to any cell that isn’t a germ cell (egg or sperm cell).
Examples of cancers:
*Skin cancer,Lung cancer
What is a point mutation?
A point mutation is a genetic mutation that involves the change, deletion or addition of a single nucleotide base in the DNA or RNA of an organism’s genome.
e.g., single nucleotide base substitution resulting in a point mutation.
What is a frame shift mutation?
One or two base pairs inserted into or deleted from the DNA.
Alterations in the reading frame of the DNA strand.
frameshift mutation
*Deletions and insertions
Describe the following point mutations within coding sequences.
- Missense mutation
- Nonsense mutation
- Missense mutations
A missense mutation is a point mutation in which a single nucleotide changes results in a codon that codes for a different amino acid.
e.g., sickle mutation
- Stop codon (nonsense mutation)
The mutation results in the presence of a stop codon in the gene sequence, which causes premature termination of the protein.
β0- thalassemia
Describe a Trinucleotide -repeat mutation.
A trinucleotide repeat mutation is a type of DNA mutation that causes a disorder when the number of repeats of three nucleotides (a triplet) increases above a certain threshold.
Describe the 4 examples of Trinucleotide -repeat mutations disorders.
- Fragile-X syndrome, 250 to 4000 tandem repeats of the sequence CGG within a gene called familial mental retardation 1 (FMR1). X linked dominant.
Macro-orchidsm, intellectual disability, long ears and face.
- Huntingdon’s disease. CAG repeat, Autosomal dominant. High dopamine
- Friedreich’s ataxia, GAA repeat, Autosomal recessive, scoliosis, Ataxia (Loss of coordination of voluntary muscle movements.)
- Myotonic dystrophy, CTG Repeat, Autosomal dominant, Cataracts, testicular hypertrophy, Can’t terminate grip.
Describe 4 interference of mutations with protein synthesis.
- Suppression of transcription
*Gene deletions
* Point mutations involving promoter sequences
- Abnormal mRNA processing
*Mutations affecting introns or splice junctions or both. - Translation
* Stop codon (chain termination mutation) creation within an exon. - Abnormal protein production without impairing any step-in protein synthesis.
Describe an example of a beneficial mutation.
- Uncommon
- HIV uses a chemokine receptor, CCR5, to enter cells, a deletion in the CCR5 gene protects from HIV infection.
Describe the following common types of DNA damage:
- Depurination
- Deamination
- Pyrimidine dimers
Common types of DNA damage
Depurination: A, G
Deamination: C⇢ U, A⇢ Hypoxanthine
Pyrimidine dimers: UV induced
Describe the following DNA repair mechanisms.
- Reversal of damage
- Excision repair
- Mismatch repair
- Recombination repair
- Error-prone repair
- Reversal of damage
Enzymatically un-do the damage.
a) Photoreactivation
b) Removal of methyl groups - Excision repair
General Process:
remove damage (base or DNA backbone)
ss nick/gap provides 3’OH for DNA Pol I initiation
DNA ligase seals nick
*Nucleotide excision repair:
Cut out a segment of DNA around a damaged base.
*Base excision repair:
Cut out the base, then cut next to the apurinic /apyrimidinic site, and let DNA Pol I repair.
- Mismatch repair
Action of DNA polymerase III (including proofreading exonuclease) results in 1 misincorporation per 108 bases synthesized.
Mismatch repair reduces this rate to 1 change in every 1010 or 1011 bases.
Recognize mis-paired bases in DNA, e.g., G-T or A-C base pairs.
These do not cause large distortions in the helix: the mismatch repair system apparently reads the sequence of bases in the DNA.
- Recombination repair
Retrieval of information from a homologous chromosome.
- Error-prone repair
Last resort for DNA repair
e.g., when repair has not occurred prior to replication.
DNA polymerase III usually dissociates at a nick or a lesion.
But replication can occur past these lesions, especially during the SOS response (“Save Our Ship”).
This trans lesion synthesis incorporates random nucleotides, so they are almost always mutations (3/4 times)
Cancer occurs following several sequential steps of abnormalities in the target cell
e.g.,
- Initiation,
- Promotion
- Progression
Describe what happens in each of these steps.
INITIATION
- Results from exposure of cells to a sufficient dose of a carcinogenic agent (initiator)
- An initiated cell is altered, making it potentially capable of giving rise to a tumor (groups 2 and 3).
Initiation alone is not sufficient for tumor formation (group 1). - Initiation causes permanent DNA damage (mutations) - rapid and irreversible and has “memory.”[group 3]
- PROMOTION
- Can induce tumors in initiated cells, but they are nontumorigenic by themselves(group 5)
- Tumors do not result when the promoting agent is appliedbefore, the initiating agent (group 4)
- Cellular changes resulting from the application of promoters do not affect DNA directly and are reversible
- Promoters enhance the proliferation of initiated cells [NB group 6]
*Promoters of carcinogenesis are substances such as phorbol esters, phenols, hormones, artificial sweeteners and drugs like phenobarbital.
How do promoters differ from initiators?
They do not damage the DNA; they enhance the effect of initiators.
State the 3 classes of carcinogenic agents have been identified.
1) chemicals
2) radiant energy
3) microbial products
All initiating chemical carcinogens are highly reactive electrophiles.
State their other characteristics.
The stages of initiation and promotion seen in the development of cancers of the liver, urinary bladder, breast, colon, and respiratory tract
- React with nucleophilic (electron-rich) sites in the cell.
- DNA, RNA, and protein targets.
- Initiation inflicts nonlethal damage on the DNA that cannot be repaired and is passed on to daughter cells.
Chemicals carcinogens can be classified into two categories.
State them.
Direct acting
Indirect acting.
