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43 Cards in this Set
- Front
- Back
Do UV rays cause DNA to break or ionization?
Are they higher or lower energy than X-rays and Gamma rays? |
No. they do not cause breaking or ionization b/c the electromagnetic waves to do not carry enough energy to break covalent DNA bonds or remove electrons.
Lower energy (longer wavelength than X- and Gamma-rays) |
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Why do HPV cases peak in the summer months?
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Immunosuppression* by UV
(think viruses) |
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What is the most common UV-DNA damage? (specificially)
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Pyrimidine dimers
T=T or C=C "TC" --> C=C is more detrimental |
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Which pyrimidine dimer is more common? more mutagenic?
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most common: T=T
mutagenic: C=C |
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What is the A-rule? What is the result?
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DNA polymerase will incorporate A across a "non-instructional" site, e.g. pyrimidine dimer
--> Tandem mutation (pyrimidine dimer and now also inappropriate C=C paired with A-A |
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What is the principal repair pathway for removal of UV-induced DNA damage?
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NER: Nucleotide Excision Repair
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What two proteins in NER detect the pyrimidine dimers?
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XPC and DDB2
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What are the three types of skin cancer? prevalence and mortality?
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basal cell carcinoma - 75%
squamous cell carcinoma - 20% melanoma - 5% (by far most mortality) |
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Where is the defect in patients with Xeroderma Pigmintosum (XP)?
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defects in nucleotide excision repair (NER)
"Nintendo XP" |
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Biologically, what is sunburn? why is this cancer protective?
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keratinocytes undergoing apoptosis --> the cells with the most heavily damaged DNA are eliminated
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* What is the cellular response to UV damage when sunburn occurs, what is missing in individuals that do not sunburn and what is result?
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UV --> Fas + FasL (ligand) --> Apoptosis
Defective --> No FasL --> no apoptosis --> no sunburn --> p53 mutations (codons 270 and 275 "hotspots") |
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What skin type is at the highest risk for skin cancer, why?
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Type II: does not burn or tan easily
no burning = damaged cells not undergoing apoptosis |
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what protects keratinocytes from UV damage?
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melanin (produced from basal layer)
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how does melanin distribution differ from light and dark skinned individuals?
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white = melanin is just a cap on the top of the nucleus of keratinocyte
dark = melanin surrounds cell |
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** What is the pathway of Melanin production?
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UV --> MSH (secreted from keratinocytes) --> MC1R (receptor on melancyte) --> cAMP --> Melanin
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What is UV-induced signaling for melanin production?
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Tanning
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* What is the key intermediate between Pheomelanin and Eumelanin?
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Dopaquinone
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* What role does cAMP play in the formation of different types of melanin?
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cAMP (from MC1R) stimulates Dopaquinone to become Eumelanin.
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* What are the two different types of Melanin?
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Pheomelanin: Red-yellow pigment
Eumelanin: Black-brown pigment |
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If cAMP is absent, what does Dopaquinone interact with and become
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interacts with cysteine to become pheomelanin
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What does Tyrosine become in the process of Melanin "differentiation"? what enzyme catalyzes?
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Dopaquinone
tyrosinase |
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** Describe the pathway of melanin formation AND then differentiation:
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Formation: UV --> MSH (secreted from keratinocytes) --> MC1R (receptor on melancyte) --> cAMP --> Melanin
Diff: Tyrosine (tyrosinase) converted to Dopaquinone --> if cAMP present --> Eumelanin --> if cAMP absent --> interacts with cysteine --> Pheomelanin ... "going cAMPing in the dark" (eumelanin) |
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What is a common defect for Type II redheads?
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MC1R: defect in pathway (cAMP) leads to inability to produce Eumelanin
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* in individuals with Type II skin, who have a MC1R defect, what is a possible therapy?
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forskolin (stimulates cAMP --> eumelanin)
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what is an additional risk for Pheomelanin? (redhead's risk)
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Pheomelanin can produce Oxidants (H2O2, O2.-)
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What is the cause of pale skin in Europeans?
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mutation in the Golden Gene [Thr111] (low number and size of melanosomes)
"The Golden Bear always gets a low score" |
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Would a European with a mutated Golden Gene and low melanin still be able to tan?
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Yes. Would have fair skin, but if Mc1r was not defective, --> Eumelanin
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What is the difference between sunburn and tanning?
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sunburn [apoptosis]
tanning [eumelanin] |
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For individuals that cannot burn, is there an increased risk for other types of cancers as well?
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Yes, increases by 30%
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What is an advantage of fair skin?
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Fair skin allows more UV-B rays in, which stimulate Vitamin D production
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What does MDM2 do?
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marks p53 for destruction
[increase MDM2 = decreased p53] |
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What is the common nucleotide change in the promoter for MDM2? what is the result?
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SNP309: G (go!) replaces T and more MDM2 is produced --> lower p53
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What role does estrogen play in MDM2 expression?
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increases affinity of Sp1 to MDM2 promoter --> increases MDM2 transcription
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* What population is most affected by a SNP309 MDM2 mutation?
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pre-menopausal women (elevated estrogen)
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What other cancer risks are present for carriers of the SNP309-MDM2?
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Increased gastic and lung cancer (more for women), colon cancer (women only)
decreased survival of other forms of cancer and certain drug resistance |
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What is the main advantage of having lighter skin?
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Vit D synthesis (UV-B necessary)
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How does a SNP309 mutation lead to lighter skin?
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SNP309 --> mutations in MDM2 --> decreased p53/melanin
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What is the precursor to MSH?
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POMC (dependent upon p53)
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* What three things does p53 stimulate in response to UV damage?
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Fas --> apoptosis
DDB2 --> pyrimidine dimer repair POMC --> b-endorphin, ACTH, MSH |
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* What three pathways/products come from POMC? what stimulates POMC?
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b-endorphin --> sun seeking behavior
ACTH --> steroids --> blocks inflammation MSH --> binds Mc1R --> tanning (from p53) |
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What gene is mutated in >80% of moles (benign melanocytes)?
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BRAF
Zach BRAF |
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What is the main cause of skin damage and cancer? (molecular level)
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Pyrimidine dimers in DNA
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What is the best predictor of skin cancer risk?
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# moles/arm
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