CARCINOGENESIS Flashcards
Outline the DNA damage response pathway
- 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
what are some exogenous DNA damaging factors?
UV light
chemical agents
what are some endogenous DNA damaging factors?
reactive metabolism intermediates
what are some types of DNA damage?
pyrimidine dimers DNA cross-links base oxidation or hydrolisation single strand and double strand breaks replication errors
Outline carcinogen activation?
pro carcinogens require metabolic activation by CYP450 to exert their genotoxic effects.
what are genotoxins?
a chemical or agent that can cause DNA or chromosomal damage
outline direct reversal of DNA damage?
damaged area is repaired directly by proteins in the body.It’s the simplest form of repair and does not require a template
what are the 2 main mechanisms of direct reversal DNA repair?
photoreactivation
alkylation
how do alkylating agents prevent cell division
by cross-linking strands of DNA
what is base excision repair?
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
what is mismatch repair?
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.
what are the 2 types of double strand break repairs?
homologous recombination and classical non-homologous end joining
outline homologous recombination?
the exchange of nucleotide sequences through use of a sister chromatid to repair damaged bases on both strands of DNA
what is non-homolohous end joining?
using microhomolgies to connect the broken ends directly without the use of a template - very prone to error!!!
what are somatic mutations?
ones that only affect that individual cell
what are germline mutations?
mutations affecting all cells of the body, including germ cells so can be inherited and passed on
what are some examples of tumour suppressor genes?
TP53
RB1
BRCA 1
BRCA 2
what is an AP site?
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.
what is retinoblastoma?
malignant tumour of retinal cells
outline the difference between herediatry and sporadic retinoblastoma causes?
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
how does pRB control the cell cycle?
It restricts the cell’s ability to replicate DNA by preventing its progression from the G1 to S phase of the cell division cycle.
what happens when pRB is phosphorylated by Cyclin D and CDK4/6?
pRB releases the E2F it was attached to which is a transcription factor which can transcribe genes needed for cell division
what happens if you get a mutation in pRB?
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.
which are the 2 mutated genes for familial breast cancer?
BRCA1 and BRCA2
