DNA Repair Flashcards
What intrinsic features of DNA protect its integrity?
Thermodynamic super molecule
Energy needed to break DNA
Nucleobases on inside of helix.
Chromatin.
What effect does cancer have on the mutation rate of cells?
Increases it.
Squamous epithelia - <1 per 10^8 base pair
In ovarian carcinoma - 75 per 10^8 base pair.
How does melanin confer protection to keratinocytes from UVR?
melanosomes carry melanin from melanocytes to keratinocytes in basal layer of epidermis - assemble into supra nuclear caps.
How does GST confer protection and what happens in cancer?
Links electrophilic compounds e.g. carcinogens to GSH –> detoxified, further metabolised and secreted. Lost from tumours due to promoter methylation.
What are the mammalian equivalents of MutS and MutL?
MSH2/MSH3 (MSH3 mutated in colon, stomach, endometrial cancers)
MLH1.
What is MGMT and how is it protective?
O6-methyl DNA methyltransferase - removes methyl and ethyl adducts from O6 of guanine.
Treat mice with methylnitrosurea –> lymphomas.
Mice with functional genes develop cancers - over expression protects.
What is synthetic lethality?
Occurs between 2 genes when loss of one is compatible with cell viability, but loss of both is lethal.
How can HR proficient tumours be sensitised to PARP inhibitors?
Suppress HR by blocking recruitment of repair proteins to DSBs.
CDK1 inactivation reduces BRCA1 focus formation and renders BRCA1 proficient tumours sensitive to PARPis.
What 2 drugs have been trialled?
Olaparib - 63% benefit in BRCA2 mutation carriers.
Iniparib + chemo - 56% clinical benefit in I group compared to chemo alone.
