Lecture 23 Flashcards
what can explain many familial cancers
inheritance of mutant tsgs
what do early stage cancer cells do and explain
find ways to eliminate wild type copies of tsgs
eg = mitotic recomb can lead to loh - can occur
can occur during g2 phase of cell cycel
Subsequent segregation of chromatics may yield a pair of daughter cells that have undergone loh
can be random but not always - can be due to improper recombination events - mitotic recomb = allows allele to be transfered = allele can end up in same cell - 2 mutated alleles = passed along to next chrom
name and describe mechanisms of loh and wt copy inactivation of tsgs
terminal deletion - wild type lost
point mutation
indels
frameshift - premature stops
describe chromatin structure
epigenetic mechanisms = no changes in dna sequence but changes in ability of dna to be expressed
tightly would arounf histones
describe heterochromatin
compact
wound up
OFF
cytosine usually methylated
transcriptionally silent
ptms can lead to dna being compacted
describe euchromatin
can be transcribed
ONN
transcriptionally accessible
where chromatin acessible
how to lose your tsgs
promoter methylation can lead to tsg inactivation without mutation
ex of epigenetic silencing - how actively gene transcribed
normal cell = fine
tumoural cell = hypermethylated and inactivated tsgs = silenced by methylation
promoter methylation can lead to tsg inactivation without mutation = epigenetic regulation of gene expression present in all genes and usually controlled for development and differentiation * dna methyl transferases = highly upregulated in cancer cells DNMT1, and DNMT3B - high upreg in highly aggressive adenocarcinoma
sometimes = give meds that prevent methylation of cytosines but not always
define epigenetic
control gene activity without changing dna sequence
what leads to p53 stabilization
dna damage and dysregulated growth signals
what is p53
tsg
form homotetramer to function - levels destabilize quickly usually
functions as a transcription factor that halts cell cycle - has dna binding domain
what are p53 targets
growth arrest genes
dna repair genes
regulators of apoptosis
Do all Tumor Suppressor Genes follow the Knudson 2-hit model??? Explains
HELL NAH
ex = p53, pten
deviates from knudson rule = loss of single tsg allele yueld abnormal cells
haploinsufficent
so one gene making p53 = not enough to do job
dicer syndrome - 2 hits needed
what does dominant negative do
mutation whose gene product adversely affects the normal wild type gene product in the same cell
usually occurs if product can still interact with same elements as wildtype product but block some aspect of its function
describe p53 - dom neg effect
normally works as tetramer
mutant p53 found in many human tumours usually carries aa substitutions in its dna binding domain
describe tsgs
regulate cell proliferation through many mechanisms
unites them is the fact that the loss of any one of them increases a cell’s selective growth advantage
act as gatekeepers - control apoptosis, cell cycle, senescence, quiescence
what happens when tsgs lost
usually affects cell phenotype only when both copies of such gene are lost - although there are exceptions that we discussed
what is synthetic lethality
combined effect of 2 alleles - each of which is non lethal but when acting in combo = results in lethality
describe how synthetic lethality found
first described by american geneticist calvin bridges in early 20th ce
Developed from genetic studies in model organisms = yeast, fruit flies
describe synthetic lethality in context of cancer
inhibiting the activity of a protein that acts downstream of the missing tumour supressor gene product along a signalling pathway
if gene a knocked out by drug and gene b is cancer mutation
= leads to cellular death since cell relies on gene a since b is cancer
Benefits to using synthetic lethality-based strategy
selective for cancer cell specific genetic mutations
strategy can be applied to any type of cancer mutation including tsgs and mutations deemed undruggable - like ras
describe translating synthetic lethality into the clinic PARP inhibitors and DNA damage repair
first synthetic lethal therapy using parp inhibitors for patients with brca1/2 mutant ovarian and breast cancers
parp does ber and brca does homologous recomb cell repair
if brca not working - parp will take over, but since brca is cancer if parp inhibited = no repair and cell death
if brca out = use parp1, if inhibit parp, fine since has other means
but if breast cancer = more dependent on parp, so use inhibitor = target brca mutated cells - synthetic lethal
describe screening for synthetic lethal interactors
oncogenic ras pushing cell
one compound that wont affect normal ras cells - does not have to affect ras pathway, can affect anything
what are hela cells
henrietta lacks
cervical cancer
cells still used to this day
immortalized = cells can divide forever
what is replicative senescence
irreversible halt in cell proliferation with retention of cell viability over extended periods of time - cells metabolically active but exited cell cycle forever
when quiescence = can go back into cell cycle
