3- instability and repair Flashcards
genomic instability
accumulation of unintended alterations to genomic sequences
genomic instability refers to an elevated _____
mutation rate
major forms of genomic instability
- gross chromosomal abnormalities
- subtle sequence changes (nucleotide instability)
what are examples of gross chromosomal abnormalities
- ploidy alterations
- gene amplification
- chromosomal structural alterations
examples of subtle sequence changes
1.point mutations
2. microsatellite instability
how do chromosomal abnormalities and mutations arise? AKA genomic instability causes
- spontaneous events
- intrinsic stresses
- extrinsic stresses
what are some consequences to damaging dna
- cell cycle arrest
- apoptosis
- cancer
- aging
- inborn disease
what the dna repair mechanisms
- double stranded dna break repair
- nucleotide excision repair
- base excision repair
- mismatch repair
- cell cycle checkpoints
DSB is produced by
free radicals , various chemicals, replication across single stranded DNA breaks
what are the 2 mechanisms for DSB repair
non homologous end joining
homologous recombination
characteristics about non homologous end joining
-potentially error prone
-critical for immunoglobulin gene rearrangement
-limited links to cancer
characteristics about homologous recombination
-precise
-highly conserved
-core factors: essential
-accessory factors: linked to disease
how does excision repair work
- recognition of damage
- removal of ssDNA containing lesion
- repair replication across gap
- ligation of the repaired strand
what are the lesions of nucleotide excision repair
bulky, helix distorting damage
what are the lesions of base excision repair
small base alterations
mech of base excision repair
-damaged base is flipped out of helix and cleaved
-recognized by endonuclease that cleaves the backbone
-polymerases can repair the site
lesions of mismatch repair
mismatches, insertion/deletion loops
mech of mismatch repair
lesions are identified by complexes and then additional factors are recruited to the damage site. the defective sequence is excised and DNA is resynthesized using the intact strand
cell cycle checkpoints=
dna damage checkpoints
cell cycle checkpoints function
- sense and respond to the presence of DNA damage by arresting cell cycle progression
- monitor and ensure completion of major cell cycle events
the mitotic spindle checkpoint ensures that
chromosomes are properly aligned on the metaphase spindle before chromosome segregation
DNA damage checkpoints respond to
genome damage by arresting cell cycle progression and promoting DNA repair
dna damage signal cascade
signal–> sensor –> transducers –> effectors –> cell cycle arrest/DNA repair/replication fork stabilization
cancer cells appear to be highly dependent on
stress response mechanisms
activated oncogenes stimulate ____ leading to DNA damage
hyperproliferation
cancer cells are susceptible to certain drugs that target
stress response pathway
senescence
DNA damage response to shorted telomeres
what is Ames test
a test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria
-tests carcinogenicity
what type of mutations are oncogenes
homozygous dominant or recessive
how do cancer cells achieve immortality
cancer cells keep high levels of telomerase, an enzyme that prevents telomerase shortening
-this gives the ability of the chromosomes to continue to replicate forever
