CARCINOGENESIS

Question 1

Outline the DNA damage response pathway

Answer 1

• DNA damage occurs which activates the kinases ATM/ATR
• These activate the checkpoint kinases
  These kinases activate p53 which then accumulates
• p53 activates p21/WAF1 which are cdk inhibitors and so arrest the cell cycle
  -This allows for DNA repair/apoptosis

Question 2

what are some exogenous DNA damaging factors?

Answer 2

UV light

chemical agents

Question 3

what are some endogenous DNA damaging factors?

Answer 3

reactive metabolism intermediates

Question 4

what are some types of DNA damage?

Answer 4

pyrimidine dimers
DNA cross-links
base oxidation or hydrolisation
single strand and double strand breaks
replication errors

Question 5

Outline carcinogen activation?

Answer 5

pro carcinogens require metabolic activation by CYP450 to exert their genotoxic effects.

Question 6

what are genotoxins?

Answer 6

a chemical or agent that can cause DNA or chromosomal damage

Question 7

outline direct reversal of DNA damage?

Answer 7

damaged area is repaired directly by proteins in the body.It’s the simplest form of repair and does not require a template

Question 8

what are the 2 main mechanisms of direct reversal DNA repair?

Answer 8

photoreactivation

alkylation

Question 9

how do alkylating agents prevent cell division

Answer 9

by cross-linking strands of DNA

Question 10

what is base excision repair?

Answer 10

recognition and removal of a single, damaged base through enzymes
DNA glycolase removes the damaged base
AP endonucleases recognise the AP site and creates a small cut in the phosphodiester backbone
DNA polymerase inserts a new base at the AP site
DNA ligase seals the small cut

Question 11

what is mismatch repair?

Answer 11

occurs when mismatched DNA pairs are incorporated into the DNA strand during replication and are not removed bu proofreading DNA polymerase. The missed errors are later corrected by enzymes which recognise and excuse the mismatched base to restore the original sequence.

Question 12

what are the 2 types of double strand break repairs?

Answer 12

homologous recombination and classical non-homologous end joining

Question 13

outline homologous recombination?

Answer 13

the exchange of nucleotide sequences through use of a sister chromatid to repair damaged bases on both strands of DNA

Question 14

what is non-homolohous end joining?

Answer 14

using microhomolgies to connect the broken ends directly without the use of a template - very prone to error!!!

Question 15

what are somatic mutations?

Answer 15

ones that only affect that individual cell

Question 16

what are germline mutations?

Answer 16

mutations affecting all cells of the body, including germ cells so can be inherited and passed on

Question 17

what are some examples of tumour suppressor genes?

Answer 17

TP53
RB1
BRCA 1
BRCA 2

Question 18

what is an AP site?

Answer 18

also known as an abasic site

a location in DNA that has neither a purine nor a pyrimidine base, either spontaneously or due to DNA damage.

Question 19

what is retinoblastoma?

Answer 19

malignant tumour of retinal cells

Question 20

outline the difference between herediatry and sporadic retinoblastoma causes?

Answer 20

hereditary causes have the first mutation present from birth in germline and second mutation occurs during life
in sporadic cases, both mutations occur during life so often has a later onset in life

Question 21

how does pRB control the cell cycle?

Answer 21

It restricts the cell’s ability to replicate DNA by preventing its progression from the G1 to S phase of the cell division cycle.

Question 22

what happens when pRB is phosphorylated by Cyclin D and CDK4/6?

Answer 22

pRB releases the E2F it was attached to which is a transcription factor which can transcribe genes needed for cell division

Question 23

what happens if you get a mutation in pRB?

Answer 23

The mutant Rb gene product is always phosphorylated and can not regulate E2F, control of cell division at the S phase does not occur, and normal cells become cancerous.

Question 24

which are the 2 mutated genes for familial breast cancer?

Answer 24

BRCA1 and BRCA2