Chemical carcinogens 2

Question 0

which UV light causes the majority of carinogenic effects?

Answer 0

UVB - 80-90% of carcinogenic dose

280-320nm

Question 1

how many people in the UK develop skin cancer each year ?

Answer 1

8000 people

Question 2

what are the different types of UV light ?

Answer 2

A- 320-400nm
B- 280-320nm
C- 200-280nm- exposed to very little of this as the atmosphere filters it out

Question 3

what strongly absorbs UVB ?

Answer 3

organic macromolecules
when it is absorbed by DNA it leads to photodimers - it can form cyclobutane pyrimidine dimers - these are formed between adjacent pyrimidine bases (T and C)

Question 4

where are the most frequent lesions induced?

Answer 4

in DNA are the cyclobutane pyrimidine dimers

• form between the 5,6 bonds on any two adjacent pyrimidines
• 5’ TpT is the most common form of damage

Question 5

what is formed in a cyclobutane dimer ?

Answer 5

it is formed due to 4 memembered ring linking elements together

Question 6

what is the estimated amount of damaging events occurring in DNA of humans every day ?

Answer 6

10 to the power of 4 - 10 to the power of 6
- however only 2% of DNA encodes for protein and in each cell there is about 6 billion bases therefore the % of damage is very small
BUT it is still a threat to the fidelity of DNA

Question 7

what is nucleotide excision repair (NER)?

Answer 7

it is an efficient repair process
it is specific for lesions that distort the helical structure of DNA
it recognises damage caused by CBPs and damage by covalent bonding such as damage caused by PAHs

Question 8

what are the 2 pathways that contribute to NER ?

Answer 8

• global surveillance for helix distortion - looks at all DNA
• transcription-coupled repair- this is more specific- it detects distortion of helical structure that prevents RNA polymerase transcribing the gene

Question 9

what does XP stand for ?

Answer 9

xeroderma pigmentosum

Question 10

what do the family of XP proteins do ?

Answer 10

they are good at finding distortions of DNA and repairing it

Question 11

what does XP do ?

Answer 11

it recognises damage and this creates a scaffold to allow DNA helicase to bind
DNA helicase binds and unwinds the DNA
incisions are made on both sides of the damage to cut out the damaged DNA
then endonucleases bind and cut out the damaged DNA
then using complementary strand, DNA polymerase resynthesises the damaged area of DNA

Question 12

what are the 2 main DNA polymerases used ?

Answer 12

delta and epsilom

- they have high fidelity so they copy with high accuracy therefore they are unlikely to insert the wrong base

Question 13

what is PCNA?

Answer 13

a trimeric protein that helps push DNA polymerase along the strand of DNA

Question 14

What are some problems with NER?

Answer 14

it can be slow and or incomplete and sometimes it doesnt detect damage

Question 15

what occurs if NER doesnt occur ?

Answer 15

trans-lesion synthesis TLS

• it is the main mechanism by which cells replicate damaged templates
• its a mechanism in which the damaged DNA is bypassed
• it uses DNA polyermases with high error rate

Question 16

what DNA polymerase is used in TLS ?

Answer 16

DNA polymerase zeta

- it has low fidelity and induces mutations into DNA- this mutation is heritable

Question 17

what does DNA polymerase zeta do in TLS ?

Answer 17

it copies around the damaged DNA

• it basically guesses the damaged area with bases
• this mechanism has evolved due to damage by UV light
• they think damage is due to thymine thymine dimer as this is the most common form of damage so it just puts in thymines and this causes a mutation

Question 18

what does UVB commonly induce?

Answer 18

C to T transitions causing a point mutation

Question 19

what does 3,4-BP induce?

Answer 19

it covalently binds to guanine so it induces G to T transitions which causes a point mutation
- this causes the bulk of the damage caused to the P53 gene

Question 20

what do mutations lead to ?

Answer 20

loss or gain of protein products

- most are loss

Question 21

what is the P53 gene ?

Answer 21

it is the tumour suppressor gene

- it encodes for the protein P53 which is a key proteins that guards the integrity of the genome

Question 22

what does DNA damage cause ?

Answer 22

it induces activity of kinase enzymes which causes phosphorylation

Question 23

what can activation of P53 by phosphorylation cause ?

Answer 23

it can kill cells and prevent cells undergoing cell division

Question 24

what can P53 cause ?

Answer 24

• increased transcription of genes for pro-apoptotic proteins
• repression of genes for anti-apoptotic proteins

Question 25

what are the 6 hallmarks of cancer?

Answer 25

1- self sufficient in growth signals - mutations that can cause a gain of function
2- insensitive to anti-growth signals- mutations leading to insensitivity
3- tissue invasion and metastasis- malignant cells are essentially parasitic cells
4- unlimited replicative potential- malignant cells
5- sustained angiogenesis- formation of new blood cells
6- evasion of apoptosis- malignant cells can evade apoptosis

Question 26

why do epithelial cells normally give rise to the damage caused by cancer ?

Answer 26

because they are constantly undergoing cell divisio

Question 27

how long can the duration of exposure be ?

Answer 27

10-30 years