genome instab + checkpoints Flashcards
what is meant by genome instability?
the elevated risk of genetic alterations
what is the mutator hypothesis?
tumour cells acquire a mutator gene (or lose an anti-mutator gene) which increases the rate of mutation as an early event in cancer development
(explains accumulation of mutations in cancer cells)
Could the absence of P53 change tolerance to mutations?
- may have an effect but must be something before this as there are an accumulation of mutations before TP53 is mutated
what are the 2 forms that tumour cell genome instability takes?
CIN - chromosomal instability
MIN - microsatellite instability
what is meant by chromosomal instability?c
chromosomal aberrations, rearrangements, large chunks of chromosomes deleted/added/moving - macroscopic changes , e.g. LOH, aneuploidy, gene amplificaiton///
what is meant by microsatellite instability?
when specific small sequences change as a result of direct mutation
e.g. point mutation, base substitution, microdeletions/insertions
How common do CIN or MIN occur?
- very rarely in normal cells - maybe once every 10 million divisions
- rate of mutations in tumour cells may be thousands times higher due to the mutator phenotype
where do mutations come from?
- DNA damage by exogenous agents e.g. ionizing radiation, UV, chemicals
- defective repair via NER, BER, DSB (messy via recombination)
- DNA damage by endogenous agents - DNA methylation, oxidation + hydrolysis
- DNA replicaiton issues
- processing errors
- inherited loss of DNA damage response/repair
give some examples of familial disorders caused by genome instability
xeroderma pigmentosum breast cancer ataxia telangiectasia NBS (vunerable to DNA damage)
what is RAD9 a paradigm for?
S/M checkpoint control
what happens when cells lack RAD9 gene (yeast cerevisea) and an extrinsic interference is added?
- there is no difference in the proliferation of normal cells and cells lacking RAD9 - appear to be healthy cells
- If impose an extrinsic interferance e.g. cdc9 temp sens mutant, cells have LOSS OF VIABILITY
what does cdc9 code for?
DNA ligase which stitches fragments of DNA together as they are synthesised
what happens to the FACs when cdc9/rad 9 mutant cells are at a restrictive temperature?
cells should stop at G2, cell cycle arrest as DNA synthsis cannot be completed due to a lack of ligase
- but as there is a loss of RAD9 cells try to undergo mitosis which results in mitotic catastrophy
what can a loss of viability screen show?
can screen for checkpoint mutations
what is a chekpoint control gene?
an extrinsic control gene which ensures viability of the cell is maintained when cells undergo stress
