Genome instability Flashcards
why is genome instability considered a hallmark of cancer?
as genome instability becomes an enabling characteristic that drives/enhances genomic alterations/mutations
what are the types of gene damage?
- Intrinsic
- Normal DNA replication
- Spontaneous base damage
- V(D) J recombination - chemical agents
- endogenous (oxygen radicals)
-exogenous (chemical mutagens) - radiation
- ionising radiation
- UV radiation
what types of DNA lesions does intrinsic gene damage cause?
base damage
base mismatches
insertions
deletions
DNA strand breaks
what types of DNA lesions does chemical agent gene damage cause?
Base modifications
Abasic sites
DNA adducts
DNA crosslinks
DNA strand breaks
what types of DNA lesions does radiation gene damage cause?
pyrimidine damage
Base modifications
Abasic sites
DNA stand breaks
what mechanism corrects DNA lesions
DNA damage response
what happens if DNA lesions aren’t corrected?
leads to genome instability
how do inherited mutations in DNA repair genes link to genome instability in cancer?
- genome instability present in precancerous lesions
- drives tumourigenesis by increasing mutation rate
- leads to mutations in oncogenes/tumour suppressor genes
what are the ways in which you can repair DNA lesions?
- base excision repair (BER)
- nucleotide excision repair (NER)
- mismatch repair (MMR)
- homologous recombination repair (HRR)
- non-homologous end joining (NHEJ)
what is single stand break repair?
responds to intrinsic - spontaneous base damage, chemical agents - exogenous (chemical mutagens)
to repair DNA lesions - base alkylation
what two types of enzymes repair base alkylation?
MGMT
ALKBH
both act directly on alkylated bases
with no steps
explain DNA repair pathways
- double stranded break (DSB) + abnormal DNA replication detected by the sensors
- signal reaches the transducer molecules
- activation of transducers
- recruit multi-functional mediator receptors
4.5 amplification of effector protein recruitment to DNA w/ multiple lesions/breaks - effector checkpoint
- DNA repair
what are some examples of sensors in DNA repair pathways?
MRN
or
RPA
what are some examples of transducers in DNA repair pathways?
ATM
or
ATR/ATRIP
what are some examples of mediators/adaptors in DNA repair pathways?
BRCA1/53BP1
or
TopBP1/claspin
what are some examples of amplifiers in DNA repair pathways?
H2AX
what are some examples of effectors in DNA repair pathways?
Chk2/p53
or
Chk1
what do BER do?
remove simple alkylation and oxidative damage
repair DNA lesions from intrinsic factors:
base damage
abasic sites
DNA SSBs
what do NER do?
removes bulky helix-distorting lesions (UV-C)
repair DNA lesions:
base modifications from chemical agents
what do MMR?
removes mis-matched bases
repair DNA lesions: from gene translation
How are DNA DSBs repaired?
- NHEJ - perform DNA DSB repair through the cell cycle
- HRR - requires homologous template for repair only in S/G2 of the cell cycle
which pathway repairs DNA DSBs faster?
NHEJ - hours - faster due to simplicity
HRR - 8-24hours - slower
what are the main ways of exploiting in genome instability in cancer treatment?
- loss of DDR pathway (genome instability)
- increased levels of replication
- increased levels of endogenous damage
how are endogenous damage caused?
increase proliferation = increase metabolic pathways = increase endogenous damage
