genome instability and mutation part 2 Flashcards
what molecules detect damage to DNA
ATM/ATR
what do ATM/ATR activate
downstream molecules such as P53, Chk1, Chk2
what are single nucleotide varients
substitution of one base at a nucleotide
what is insertion or deletion
gain/loss of one or hundreds of nucleotides
what are translocations
rearrangement of non homologous chromosomes
what is aneuploidy
gain or loss of entire chromosomes
what is microsatellite instability
variation in short repeats found in the genome
mutations: common single nucleotide varient
P53 point mutations
mutations: insertions and deletions in cancer
many oncogenes are mutated or amplified and TSGs are deleted or inactivated
mutations: inversions
section of DNA flips itself around
mutations: aneuploidy
if the mitotic checkpoint isn’t working then there is not proper chromosome segreation
mutations: microsatellite instability
highly variable from person to person, set length in individuals so can be genetic fingerprint, the sequences become unstable and can shorten or lengthen
when does microsatellite instability occur
when there is a defect in mismatch repair
why are mutations important?
when they can confer a selective advantage to cells e.g. increase proliferation and decrease apoptosis often have a selective advantage and result in clonal cancer
mutations and cancer
they drive cancer and make it become more aggressive overtime and resistant to treatment
which genes are commonly mutated in cancer
P53 and other TSGs are inactivated, RAS and EGFR are mutated oncogenes
what happens if theres a mutation in a damage and response gene (‘caretaker genes’)?
less protective mechanisms in the cell so it becomes more prone to further mutation etc…
tumour heterogeneity
different genotypes and phenotypes within a cancer due to different mutations within different cells. Different mutations are selected for.
UV light and skin cancer
UV light is absorbed by pyrimidine bases which makes them reactive and if its next to another pyrimidine it can form pyrimidine dimers e.g. c-c
smoking and lung cancer
smoking causes bulky and oxidative (small adducts) damage. risk of P53 mutations strongly associated with heavy tobacco consumption. Polycyclic aromatic hydrocarbons in the smoke causes mutations at sites susceptible to adducts
infections and cancer
infections are associated with inflammation (increase ROS) and can induce DNA damage
what cancer stems from hepatitis B/C
liver
what cancer is associated with helicobacter pylori
stomach
functional redundancy in DNA repair pathways
when one pathway does not work, the cell can alter DNA so that another pathway repairs the DNA
what happens when DNA damage response pathways fail
only somatic mutations tend to occur and they result in mutator phenotype and cancer
what repair pathway is used for hereditary nonpolyposis colorectal cancer and what mutations occur
MMR, mutations in MutS/MutL which can be detected by MSI
what repair pathway is used for hereditary breast and ovarian cancer and what mutations occur
DSBR, BRCA1/2 genes are mutated which are important in homologous recombination pathway
what repair pathway is used for xeroderma pigmentosum and what mutations occur
NER, bulky adducts result in slow neurodegeneration
what repair pathway is used for cockayne syndrome and what symptoms
NER, sensitivity to sunlight and growth retardation
what repair pathway is used for Li Fraumeni and what mutations occur
DNA damage sensing, P53 mutation
what repair pathway is used for Ataxia telangiectasia and what mutations occur
DNA damage sensing, ATM mutation
