Into to tumor suppressor genes Flashcards
What are tumor supressor genes
tsg encode proteins that maintain checkpoints and control genome stability through apoptosis, and repairing dna damage
history of tsg
henry harris 1969
fused normal cells with tumor cells formed hybrid cells incapable of forming tumors hence tsg theorised
rb1 first tsg identified 1986
knudsons two hit hypothesis
development of retinoblastoma required two mutations
- now known to be loss of functional copies of tumor suppressor gene
most loss of function in TSG are recessive in nature aka one normal allele is enough for control
second hit needed to disrupt function
TSG inactivation
associated with heritable cancer
loss of heterozygosity due to loss of an allele
TSG functions
oncogenes antagonist
block proliferation - cell cycle inhibitor/ repression of transcrip factors or activation
DNA repair
Induce apoptosis
DNA repair Genes
encode dna repair enzymes detect and repair errors in dna due to damage aka DSBs
repaired by homogulose combination
DNA repair genes defects
knocout of dna repair function of 1 or more leads to sequential acquisition of more mutations
defects in dna repair genes cause genomic instability and accelerate activation of onocgenes and loss of TSG
high mutational load in inherited defects
BRCA 1 and 2
Repair DNA double strand breaks by homogulous recombination
breast cancer - 55-65% are mutated brack 1 and 45% of them mutated on BRCA2
increase risk of breast cancer but also ovarian,prostate e.g.
Synthetic lethality
PARP repairs single stranded breaks in DNA if PARP is inhibited a Double stranded break is caused this leads to BRCA 1 and 2 being used to fix it. in mutated BRCA cell this does not happen and leads to cell death
Tp53
detects cellular stress etc dna dmage
induces g2 cell cycle arrest
causes apoptosis if repair fails
TP53 part 2
high levels actually due to inactive p53 protein
normal p53 regulated by negative feedback
p53 induces mdm2 - mdm2 protein binds p53 - targets p53 to destruct
phophorylation of p53 disrupts this complex
why is p53 important
most commonly affected TSG
most affected by missense mutations in DNA binding domain
tp53 mutations
express a dominant type of mutation
loss of one allele maybe enough
tp53 missense mutations reduce binding of wild type tp53 mutants to p53 responsive elements
Li-fraumeni
germline missense p53 mutations associated with early age onsent
paitents are predisposed to cancer and has wide variabilty of cancer aka breast, lung etc
therapeutic small molecules
small molecules mira1 and prima 1 maybe able to restore wild type p53 function
