Flashcards in Chemical carcinogens 2 Deck (28):
how many people in the UK develop skin cancer each year ?
which UV light causes the majority of carinogenic effects?
UVB - 80-90% of carcinogenic dose
what are the different types of UV light ?
C- 200-280nm- exposed to very little of this as the atmosphere filters it out
what strongly absorbs UVB ?
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)
where are the most frequent lesions induced?
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
what is formed in a cyclobutane dimer ?
it is formed due to 4 memembered ring linking elements together
what is the estimated amount of damaging events occurring in DNA of humans every day ?
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
what is nucleotide excision repair (NER)?
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
what are the 2 pathways that contribute to NER ?
- 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
what does XP stand for ?
what do the family of XP proteins do ?
they are good at finding distortions of DNA and repairing it
what does XP do ?
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
what are the 2 main DNA polymerases used ?
delta and epsilom
- they have high fidelity so they copy with high accuracy therefore they are unlikely to insert the wrong base
what is PCNA?
a trimeric protein that helps push DNA polymerase along the strand of DNA
What are some problems with NER?
it can be slow and or incomplete and sometimes it doesnt detect damage
what occurs if NER doesnt occur ?
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
what DNA polymerase is used in TLS ?
DNA polymerase zeta
- it has low fidelity and induces mutations into DNA- this mutation is heritable
what does DNA polymerase zeta do in TLS ?
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
what does UVB commonly induce?
C to T transitions causing a point mutation
what does 3,4-BP induce?
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
what do mutations lead to ?
loss or gain of protein products
- most are loss
what is the P53 gene ?
it is the tumour suppressor gene
- it encodes for the protein P53 which is a key proteins that guards the integrity of the genome
what does DNA damage cause ?
it induces activity of kinase enzymes which causes phosphorylation
what can activation of P53 by phosphorylation cause ?
it can kill cells and prevent cells undergoing cell division
what can P53 cause ?
- increased transcription of genes for pro-apoptotic proteins
- repression of genes for anti-apoptotic proteins
what are the 6 hallmarks of cancer?
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
why do epithelial cells normally give rise to the damage caused by cancer ?
because they are constantly undergoing cell divisio