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What are the 2 ways that mutations that drive cancer actually come from?
1. Damaging mutagenic events that get missed by the DNA repair pathways
2. Damaging mutagenic events that can't be repaired because of inactivated DNA repair pathways
What are the 6 gatekeeper tumor suppressors?
Rb, NF1, APC, p53, PTEN VHL
What are the 4 caretake tumor suppressors?
BRCA1/BRCA2, p53, MSH2, MGMT
What is the definition of a tumor suppressor?
Normal genes that function to slow down growth/proliferation, allow for cell death, and maintain integrity of the genome.
The loss or inactivation of tumor suppressor genes is a significant event in the development of cancer.
What is the goldilocks principle of cancer?
Developing cancer wants to have just enough genomic instability to promote easy acquisition of mutation, but not too much to cause death
Which cell types incur initiating pro-tumorigenic mutation?
Self-renewing stem cells OR undifferentiated transit-amplifying cells
Why is a mutation in the stem cell particularly problematic?
Stem cells represent the only stable repository of genetic information in tissue.
Because of self-renewing nature of stem cells, mutation will always be present in the cell.
What are the mechanisms to protect stem cells?
1. Shielding from harm: keep the undifferentiated/stem cells at bottom of crypt, protect from things from outside environment. Cells that accrue mutations will be sloughed off. Goblet cell-secreting mucin helps protect also.
2. Infrequent mitoses of stem cells: minimization of cell divisions protects them from potential harm associated with replication.
3. Asymmetric cell division of stem cells: Stem cell produces 1 stem cell and 1 transit amplifying cell. New copy of DNA goes to transit amplifying, old copy goes to stem cell -> protects genome of stem cells.
What cancer type derives specifically from stem cells?
Squamous cell carcinoma
Skin composed of two main layers: epidermis and dermis.
Keratinocytes in skin die 20-30 days after being formed from epidermal stem cells.
What experimental evidence suggests that squamous cell carcinoma derives from epithelial stem cells?
Painting mouse skin with initiator and promoter: took 3 months-1 year between paintings for papilloma to occur.
Cells "remembered" exposure.
Suggests that mutation occurred in self-renewing stem cells and transit-amplifying cells.
How to test for experimentally:
Use 5-FU to selectively kill actively cycling cells.
What are the 3 intracellular defense mechanisms in the second line of defense to protect the integrity of the genome?
1. Efflux pump
2. Physical shield provided by intracellular molecules
3. Repairing improperly replicated or damaged DNA
What are the 2 tissue-level organization/physiology mechanisms in the first line of defense to protect the integrity of the genome?
1. Anatomically shielding stem cell compartment from harm
2. Infrequent mitoses + asymmetric division of stem cells
Efflux pumps are lost upon _____. Why?
Efflux pumps pump out potentially mutagenic compounds that may have entered cell. Tissue resident stem cells contain high levels of efflux pumps.
Why they are lost after differentiation: too much energy cost to keep them
Cancer cells can also gain access to pumps during some drug treatments
How do cancer cells acquire mutations?
If cells have potential to express it, and cancer cells can use it, they will find a way to acquire it!
One mechanism of bacterial antibiotic resistance is efflux pumps
What defense mechanisms did humans evolve to protect ourselves from sun/ UV radiation?
Melanin production, DNA damage pathways that likely evolved for UV-induced DNA damage
Why did humans evolve to have less hair?
To prevent overheating as the planet got warmer
Why did lighter skin evolve?
Some amount of UV radiation is required to produce vitamin D in the body
How does melanin protect cells from harmful radiation?
Melanocytes, finger like cells located at bottom of epidermis, store melanin within cells in granules called melanosomes
UV detection -> epithelial cells release alpha-MSH -> melanocytes release melanosomes to be taken up by epithelial cells above -> accumulation of melanin in keratinocytes -> darkening of skin -> protects DNA of epithelial cells from UV damage
alpha-MSH also activates what?
mitogenic pathways inside melanocytes
Produces brown/black hue
How can melanoma occur?
Mitogenic tumor promotion from activation of growth-promoting pathways (alpha MSH activates Ras pathway) combined with mutation from penetrating UV light (cancer of melanocytes)
Melanoma only makes up __% of skin cancers
But responsible for majority of skin cancer deaths each year
Why are light skinned individuals more at risk of melanoma?
They still have active melanocytes (like dark skinned) but produce LESS TOTAL melanin and have a higher ratio of pheomelanin (red/pink color) to eumelanin (black/brown color)
Pheomelanin doesn't provide as good protection from UV radiation + melanocytes are still active from UV -> high risk of melanoma
What are the types of DNA damage?
a) DNA replication errors
b) Intracellular molecules
What are 2 primary ways DNA defects can arise during replication?
1. Incorrect base incorporation by DNA polymerase
2. Replication stress leading to double stranded break formation
DNA polymerase error rate is
1 mistake in 10^5 nucleotides
How does DNA polymerase fix errors?
DNA polymerase has proofreading ability
Has polymerase domain and proof-reading domain
How to test experimentally: Mutate proof-reading domain
How does mismatch repair work?
Mismatch repair is the backup if DNA polymerase proofreading does not catch the mismatched bases. Catches "stuttering" errors
Group of proteins (MSH proteins) can identify and bind to the mis-paired base
Second complex (MLH proteins) cuts DNA near the mismatch and cleaves the incorrect nucleotide and a surrounding patch of DNA
DNA polymerase than replaces missing section with correct nucleotides
Colon cancer has been shown to acquire mutations in ______
Inactivation of MMR protein MSH2 (caretaker tumor suppressor gene) leads to rapid accumulation of mutations resulting from unprepared mismatches (genomic instability)
What intracellular biochemicals are the most problematic for DNA damage?
O2 and H2O
What are the two most common spontaneous reactions of DNA bases in aqueous systems?
Depurination: chemical bond linking purine to deoxyribose sugar can undergo spontaneous hydrolysis in water
Deamination: amine group turns to carbonyl group -> structural changes nucleotides to something else example cytosine -> uracil
Why are oxidations and deaminations so problematic?
C->T mutation will pair with adenine
G->T mutation will also pair with adenine
Unrepaired deamination or oxidations can cause the wrong base to appear in the nucleotide sequence if replication were to occur without fixing the problem
Practice Problem: What would happen if the cytosine in the DNA sequence 5' TGGCAGGAG 3' underwent spontaneous deamination to a uracil and was not repaired? Supposed this mutated sequence was part of the APC tumor suppressor gene - provide one hypothesis of how this would lead to colon cancer?
5' TGGCAGGAG 3' would result in 5' TGGTAGGAG 3' following replication of the unrepaired DNA sequence. Amino acid would be changed from Trp-Gln-Glu to Trp-STOP -> nonsense mutation -> truncation of protein. If APC were truncated, it likely will no longer be able to function to bind to Beta-Catenin -> promote TCF activatation -> avoid differentiation (Step 1 of colon cancer progression)
What are the 3 types of point mutations?
Silent: no effect on protein
Missense: results in an amino acid substitution (can be conservative or non-conservative)
Nonsense mutation: substitutes a stop codon for an amino acid
What are two reasons DNA damage might not be repaired?
1. Too much damage for cell to effectively repair all of it
2. Inactivated repair machinery
How might amino acid redundancy in genetic code be a fail safe against cancer?
If you have a mutation, good change it will be silent and have no impact on the amino acid sequence
Base Excision Repair
Enzymes recognize chemically altered bases that have minimal helical distortion effect
DNA glycosylase cleaves the glyosidic bond between altered base and deoxyribose
AP endonuclease removes base free sugar
Resulting gap filled by DNA polymerase and DNA ligase
What are the 3 specialized DNA glycosylases
1. UDG's uridine glycosylase -> gets rid of uracil that's not supposed to be there
2. OGG 8-oxoguanine glycosylase -> removes oxidized guanine
3. Thymine glycosylase -> gets rid of deaminated methyl cytosine
Defects in DNA glycosylases promote
genomic instability and cancer
Cancer cells that have defects in BER enzymes are highly genomically unstable and prone to frequent mutations
What are two main sources of damaging radiation that our cells can be exposed to?
1. UV Radiation: important environmental mutagen
2. X-ray radiation: very little natural exposure
What is the most likely outcome of UV damage to the DNA?
Production of pyrimidine dimer
UV light induces adjacent pyrimidine nucleotides (C or T) to become covalently joined as a pyrimidine dimer
Causes bulky distortion in helix, making DNA replication problematic
What is XPC?
Protein target of p53, critical for detection of bulky lesion and recruiting other proteins important for NER
Nucleotide excision repair
Mechanism by which cell can repair bulky helix distortions
UV radiation produces thymine dimer -> detection by XPC -> surrounding DNA opened up -> enzymes cut damaged region -> DNA polymerase fills in gap with new nucleotides
If NER is inactivated by loss of p53 or loss of NER-specific genes (XP family members), cell is forced to try to replicate over bulky legions
Bypass synthesis is error prone
Rare autosomal recessive disease
Inherited mutations in many XP family member genes
Have 10,000-fold increase risk for developing various type of skin cancer
What are three common chemicals that can alter the structure of DNA
1. Alkylating agents
2. Polycyclic aromatic hydrocarbons
3. Heterocyclic amines
What are alkylating agents?
Agents that attach alkyl (hydrocarbon) groups to DNA
Alkylation of guanine leads to G->A mutation
Mustard gas is the most well known alkylating agent
What are nitrosamines
Source of DNA alkylation
Produced from nitrites and nitrates found in many food products
Nitrates used as preservatives in many processed foods (especially meats)
What is MGMT?
MGMT is an enzyme that dealkylates DNA
MGMT promoter hypermethylation has been observed as a relatively early event in some types of colon cancers
Ethyl guanine has a high propensity to bind to thymine
G->A mutations have been shown to promote oncogenic KRas mutation in some colon cancer
How do dietary carcinogens cause colon cancer?
1. Dietary nitrites and nitrates converted to alkylating nitrosamine compounds
2. Nitrosamines can alkylate guanine, pairs with T, leads to G-> A mutation
3. Alkylation of KRas gene by nitrosamine will not be fixed by MGMT b/c it is often inactivated early in progression of colon cancer
G->A mutation in KRas promotes constitutive activation
How to treat MGMT inactivated cancer?
MGMT silencing makes cancer vulnerable to alkylating chemotherapeutics
Cancer driven by alkylation by causing more alkylation "Hitting it where it's already weak"
Polycyclic Aromatic Hydrocarbons
Benz[a]pyrene product of cigarette smoke
Activated benzo[a]pyrene can form DNA adducts with guanine
Lesion bulky enough to require NER not BER
Sometimes NER won't catch
Error prone repair through bulky lesion can lead to G->T mutation -> frequently found in p53 DNA binding domain of smokers
p53 is important for
nucelotide excision repair because it drives transcription of XPC
When p53 is inactivated, more likely to get mutations in
Nucleotide excision repair pathway
______ Transversions in p53 and smoking
known to result from the interaction of BPDE with guanine
Commonly found in DNA binding domain of p53 gene in smokers
What are heterocyclic amines?
Meat cooked to high temperatures can cause cancer
Heterocyclic amines are formed when amino acids and creatine react at high temperatures
Creates bulky lesions that require NER, but properly corrected more often than Benz[a]pyrene adducts
Replication fork stalling can result in
DNA double stranded breaks (DSBs)
DNA replication is thought to be the major source of DSBs in proliferating cells since the DNA at replication forks is fragile and susceptible to breakage
Excess proliferative rate has been correlated with higher propensity for DSBs
What also causes DSBs in DNA, other than replication fork stalling?
Effective way to repair DSBs
1. BRCA1 binds to DNA in response to double stranded breaks
2. BRCA1, BRCA2 along with many other proteins can work to initiate homologous recombination to fix DSB
BRCA1/BRCA2 likely serve as a molecular scaffolding for other proteins involved in homologous recomination
Non Homologous End Joining (NHEJ)
Backup to homologous recombination but results in nucleotide deletion
By inactivated HR proteins cancer can force the cell to rely on the less effective NHEJ to repair DSBs -> genome instability
What happens when NHEJ doesn't work
Free chromosomal ends created from DSB can randomly fuse to other chromosomes -> unrepaired breaks are likely a source of chromosomal translocation
BRCA1 in human cancer
50% of hereditary breast cancer cases associated with mutations in BRCA1/BRCA2
BRCA1/2 follow Knudson's 2-hit hypothesis with susceptible individuals being born with one mutated copy and losing the other likely via LOH
How to treat BRCA1/BRCA2 mutated cancer?
Ramp up double stranded DNA breaks
Platinum chemotherapy which causes double stranded breaks
Do tamoxifen or aromatase inhibitors work on BRCA1/2 related breast cancer?
BRCA1/2 is likely to be ER-negative, so tamoxifen and aromatase inhibitors will not work
BRCA1/2 mutation likely occurred in stem cell prior to differentiation, which is why they are usually ER negative
How does BRCA1/2 mutated cancer adapt to therapy?
Develop acquired resistance by reversing original BRCA1/2 genetic mutations if this allows cancer to survive
Defects in which of the following cellular processes may contribute to an increased incidence of cancer?
a. Nucleotide excision repair
b. Mismatch repair
c. Base- excision repair
d. All of the above
e. None of the above
d. all of the above
2. Which of the following is not a feature of tissue stem cells
a. high expression of efflux pumps
b. asymmetric division
c. high rate of cell division
d. located in a protected niche
e. none of the above
c. High rate of cell division
3. What is the function of MGMT
a. removes all alkyl groups from DNA
b. removes amino groups from DNA
c. repairs bulky adducts on DNA
d. metabolizes carcinogens in the liver
e. none of the above
a. Removes alkyl groups from DNA
4. Which of the following genes is a transcriptional target of p53?
a. DNA polymerase
e. B and D
5. Explain how the experiments using DMBA and TPA helped uncover which type of cell (stem, transit amplyfying
Takes over a year for cancer to develop
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