Path - Uv Radiation

Front 1

Do UV rays cause DNA to break or ionization?

Are they higher or lower energy than X-rays and Gamma rays?

Back 1

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)

Front 2

Why do HPV cases peak in the summer months?

Back 2

Immunosuppression* by UV

(think viruses)

Front 3

What is the most common UV-DNA damage? (specificially)

Back 3

Pyrimidine dimers

T=T or C=C

"TC" --> C=C is more detrimental

Front 4

Which pyrimidine dimer is more common? more mutagenic?

Back 4

most common: T=T

mutagenic: C=C

Front 5

What is the A-rule? What is the result?

Back 5

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

Front 6

What is the principal repair pathway for removal of UV-induced DNA damage?

Back 6

NER: Nucleotide Excision Repair

Front 7

What two proteins in NER detect the pyrimidine dimers?

Back 7

XPC and DDB2

Front 8

What are the three types of skin cancer? prevalence and mortality?

Back 8

basal cell carcinoma - 75%
squamous cell carcinoma - 20%
melanoma - 5% (by far most mortality)

Front 9

Where is the defect in patients with Xeroderma Pigmintosum (XP)?

Back 9

defects in nucleotide excision repair (NER)

"Nintendo XP"

Front 10

Biologically, what is sunburn? why is this cancer protective?

Back 10

keratinocytes undergoing apoptosis --> the cells with the most heavily damaged DNA are eliminated

Front 11

* What is the cellular response to UV damage when sunburn occurs, what is missing in individuals that do not sunburn and what is result?

Back 11

UV --> Fas + FasL (ligand) --> Apoptosis

Defective --> No FasL --> no apoptosis --> no sunburn --> p53 mutations (codons 270 and 275 "hotspots")

Front 12

What skin type is at the highest risk for skin cancer, why?

Back 12

Type II: does not burn or tan easily

no burning = damaged cells not undergoing apoptosis

Front 13

what protects keratinocytes from UV damage?

Back 13

melanin (produced from basal layer)

Front 14

how does melanin distribution differ from light and dark skinned individuals?

Back 14

white = melanin is just a cap on the top of the nucleus of keratinocyte

dark = melanin surrounds cell

Front 15

** What is the pathway of Melanin production?

Back 15

UV --> MSH (secreted from keratinocytes) --> MC1R (receptor on melancyte) --> cAMP --> Melanin

Front 16

What is UV-induced signaling for melanin production?

Back 16

Tanning

Front 17

* What is the key intermediate between Pheomelanin and Eumelanin?

Back 17

Dopaquinone

Front 18

* What role does cAMP play in the formation of different types of melanin?

Back 18

cAMP (from MC1R) stimulates Dopaquinone to become Eumelanin.

Front 19

* What are the two different types of Melanin?

Back 19

Pheomelanin: Red-yellow pigment

Eumelanin: Black-brown pigment

Front 20

If cAMP is absent, what does Dopaquinone interact with and become

Back 20

interacts with cysteine to become pheomelanin

Front 21

What does Tyrosine become in the process of Melanin "differentiation"? what enzyme catalyzes?

Back 21

Dopaquinone

tyrosinase

Front 22

** Describe the pathway of melanin formation AND then differentiation:

Back 22

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)

Front 23

What is a common defect for Type II redheads?

Back 23

MC1R: defect in pathway (cAMP) leads to inability to produce Eumelanin

Front 24

* in individuals with Type II skin, who have a MC1R defect, what is a possible therapy?

Back 24

forskolin (stimulates cAMP --> eumelanin)

Front 25

what is an additional risk for Pheomelanin? (redhead's risk)

Back 25

Pheomelanin can produce Oxidants (H2O2, O2.-)

Front 26

What is the cause of pale skin in Europeans?

Back 26

mutation in the Golden Gene [Thr111] (low number and size of melanosomes)

"The Golden Bear always gets a low score"

Front 27

Would a European with a mutated Golden Gene and low melanin still be able to tan?

Back 27

Yes. Would have fair skin, but if Mc1r was not defective, --> Eumelanin

Front 28

What is the difference between sunburn and tanning?

Back 28

sunburn [apoptosis]

tanning [eumelanin]

Front 29

For individuals that cannot burn, is there an increased risk for other types of cancers as well?

Back 29

Yes, increases by 30%

Front 30

What is an advantage of fair skin?

Back 30

Fair skin allows more UV-B rays in, which stimulate Vitamin D production

Front 31

What does MDM2 do?

Back 31

marks p53 for destruction

[increase MDM2 = decreased p53]

Front 32

What is the common nucleotide change in the promoter for MDM2? what is the result?

Back 32

SNP309: G (go!) replaces T and more MDM2 is produced --> lower p53

Front 33

What role does estrogen play in MDM2 expression?

Back 33

increases affinity of Sp1 to MDM2 promoter --> increases MDM2 transcription

Front 34

* What population is most affected by a SNP309 MDM2 mutation?

Back 34

pre-menopausal women (elevated estrogen)

Front 35

What other cancer risks are present for carriers of the SNP309-MDM2?

Back 35

Increased gastic and lung cancer (more for women), colon cancer (women only)

decreased survival of other forms of cancer and certain drug resistance

Front 36

What is the main advantage of having lighter skin?

Back 36

Vit D synthesis (UV-B necessary)

Front 37

How does a SNP309 mutation lead to lighter skin?

Back 37

SNP309 --> mutations in MDM2 --> decreased p53/melanin

Front 38

What is the precursor to MSH?

Back 38

POMC (dependent upon p53)

Front 39

* What three things does p53 stimulate in response to UV damage?

Back 39

Fas --> apoptosis

DDB2 --> pyrimidine dimer repair

POMC --> b-endorphin, ACTH, MSH

Front 40

* What three pathways/products come from POMC? what stimulates POMC?

Back 40

b-endorphin --> sun seeking behavior

ACTH --> steroids --> blocks inflammation

MSH --> binds Mc1R --> tanning

(from p53)

Front 41

What gene is mutated in >80% of moles (benign melanocytes)?

Back 41

BRAF

Zach BRAF

Front 42

What is the main cause of skin damage and cancer? (molecular level)

Back 42

Pyrimidine dimers in DNA

Front 43

What is the best predictor of skin cancer risk?

Back 43

# moles/arm