Exploiting DNA damage Response Flashcards
6 types of DNA damage
Single strand break Double strand break Vase modification Base cross links/addicts A basic sites Base mismatch
What damage does replication stress cause?
Double strand break
What damage does ionising radiation cause?
Single strand break
Ds break
Base modification
What damages does metabolism cause
Ds break
Base modification.
Base cross links/adducts
What damage does UV light cause?
Base cross links and adducts
What damage do abasic sites cause
Single strand break
What caused base mismatch
DNA replication error
What are abasic sites caused by
Instrinsif molecular instability
What do cells do when they experience DNA damage?
Initiate DDR
What is DDR?
A network of cellular pathways that sense, signal and repair the DNA lesion
7 types of DNA Damage repair
Base excision repair Non homologous end joining Homologous recombination Nucleotide excision repair Franconi Anemia Direct reversal Mismatch repair
What does base excision repair work on?
Ss breaks
Abasic sites
Base oxidation/ alkylation
NHEJ is used in
Double strand breaks
HRR is used in
Double strand break
Nucleotide excision repair is used in
Single strand break
Base oxidation/ alkylation
Base cross link adducts
FA is used in
Base cross links/adducts
Direct reversal is used in
Base oxidation/ alkylation
Mismatch repair fixes
Base mismatch
What is therapeutic index
Differential in dose of a therapeutic agent that causes the therapeutic response to the amount that caused unmanageable adverse effects
What is therapeutic window
Range of doses that produces response without causing any significant adverse effect in patients
3 examples of alkalyting agents
Cyclophosphamide
Do I
Temozolomid
What do alkalyting agents cause
Simple and complex base adducts
2 examples of platinum salts
Cisplatin
Carboplatin
What do platinum agents caused
Complex base adducts
2 examples of antimetabolites
Methotrexate
5-FU
What do antimetabolites cause?
Double strand breaks - replication associated
2 examples of genotoxic natural products
Doxorubicin and bleomycin
What do genotoxic natural products cause 2/3
DNA binding/ intercalation
Topoisonerase inhibition
3 topoisomerase inhibitors
Irinotecan
Comprothecin topo1
Etoposide topi 2
What are BRCA1 and 2?
Tumour suppressor genes when mutated lead to hereditary breast cancer
What kind of mutations cause TNBRC BRCA?
Germ line LOF mutations
What kind of mutations can we find in brca in sporadic triple negative breast cancer?
Deleterious
What do BRCA genes do?
Repair DS breaks by HRR AND FA
What is PARP1?
Component of nucleotide excision repair involved in removal of base adducts
What does inhibition of PARP1 do?
Prevents repair base modification using bulky adducts
Current BRCA cancer approved drugs 2
Olaparib
rucaparib a
How is Rb involved in DNA repair?
NHEJ
What does Rb do?
Tumour suppressor gene executing G1 checkpoint control
4 cancers with somatic deleterious Rb
Sarcoma
Glioblastoma
SCLC
HR prostate
