FABIAN 3 Flashcards
what is heterochromatin vs euchromatin?
heterochromatin: tight, inactive
euchromatin: loose, active
what can lead to TSG inactivation without mutation?
epigenetic
promoter methylation
inactivates the gene
-> cancer
what proteins are responsible for DNA methylation?
DNA methyl transferases (DNMTs)
upregulated in cancer cells
how does DNA damage and dyregulated growth affect p53?
leads to p53 stabilisation (normally unstable)
p53 forms a tetramer to function
functions as a transcription factor that halts the cell cycle
targets genes that include growth arrest genes, DNA repair genes, regulators of apoptosis
what is special about p53 in terms of the knudson two hit rule?
one wild type copy of p53 is not enough to be sufficient
the loss of a single allele will yield abnormal phenotypes
what does dominant negative mean?
a mutation whose gene product adversely affects the normal wild type gene product within the same cell
p53 works a tetramer, so one bad subunit ruins everything
mutant p53 in human tumours carries AA substitutions in its DNA binding domain
what is synthetic lethality?
the combined effect of two alleles each of which is non lethal but when combined they result in death
genetic pathways of those two genes are linked through downstream effect
what are the benefits of using synthetic lethality based treatment?
selective for cancer cell specific genetic mutations
can be applied to any type of cancer mutation including TSGs and mutations that are “undruggable”
what are the two genes that are involved in different DNA repair mechanisms?
BRCA is needed for homologous recombination
PARP1 is used in base excision repair
(you need to delete one and treat the other one with drug to kill the cancer cell)
look at slide 85 for visual explanation
how can synthetic lethal interactions be screened for?
take the wild type and the mutant and subject it to different compounds from a small molecule library, find what kills wild type and mutant only, or both
what are the two major obstacles to cell immortalisation?
- replicative senescence: an irreversible halt in cell proliferation with retention of cell viability over extended periods of time (active but exits the cell cycle forever)
- crisis: genetic catastrophe, leads to death by apoptosis
what triggers senescence? (one of the triggers)
telomere shortening
more p53
senescence
can be bypassed by disruption of tumour suppressive pathways (p53 and rb)
what happens after senescence bypass?
cells undergo crisis
chromosomes fuse and that leads to apoptosis
asynchronous event
what is the mechanism of breakage-fusion-bridge?
no telomeres but the cell still divides
unprotected chromatid ends
end to end fusion
anaphase causes a snap, breaks the chromatids
there is a new point of fusion
a new genetic product
another break
that kills the cell
how can cancer cells escape crisis and what happens after that?
escape crisis by expressing telomerase enzyme to keep long telomeres
cells that have escaped crisis can indefinitely proliferate and are said to be immortalised
