DNA damage and repair Flashcards
Name some endogenous sources of DNA damage
free radicals
replication error
Name some exogenous sources of DNA damage
alkylating agents
mutagenic agents
anticancer drugs
free radicals
Name some types of DNA damage
missing base (apurinic site) deamination mismatch DDB Pyrimidine dimer inter-calculating agent bulki adduct interstrand crosslink SSB
define replication stress
inefficient replication that leads to the replication fork slowing, stalling and/or breakage
Give 4 reasons for replication stress
replication machinery defect replication fork progression hinderance repetitive DNA (forward and backward slippage) defects in response pathways
What are the three normal results of dna damage/ replication stress ?
senescence ( permanent cell cycle arrest)
apoptosis
DNA repair
Explain base excision repair
deamination of base
uracil detected
removed uracil
DNA correction by polymerase and ligase
Explain nucleotide excision repair
UV causes thymidine dimer
detected DNA opened to form a bubble
damage region cut out of bubble
DNA polymerase and ligase replace
Explain mismatch repair
mismatch detected
new DNA strand cut
mispaired nucleotide and its neighbours removed
replace by dna polymerase and ligase
What are the two ways double stranded breaks are fixed? When is each method used?
non homologous end joining
homologous end joining
depend on what point in cell cycle damage occurs as to which method is used
Explain non-homologous end joining. what is the problem with it?
damage end of dna cut off ligase then joining ends together
prone to mutation
could removed important sections of DNA
Explain homologous end joining.
exonucleases act in single strnad
single strand can invade helix and form d loop and holliday junction
uses other dna strand as template for repair
What makes some tumours receptive to dna treatment but the recurrence?
tumour heterogencity
differential sensitivity to chemotherapy drugs
chemotherapy induced mutagenesis
What is synthetic lethality strategy? What is an example?
look in detail at cancer cell line to determine which pathways affected
can then use specific drugs to target pathways which will then induce cell death
For example in individuals homozygous for defective BRCA gene if PARP inhibitors induce DDB that cannot be fixed synthetic lethality is induced
