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Title: Studies of PARP-1 activation and inhibition using NMR spectroscopy
Author: Ogden, Tom
ISNI:       0000 0004 8500 5926
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Poly(ADP-ribose)polymerase 1 (PARP-1) is a highly abundant multi-domain chromatin-associated enzyme found in all higher eukaryotic cell nuclei. It is the founding member of the PARP family of enzymes that modify themselves and other proteins by adding negatively charged poly(ADP-ribose) chains derived from NAD+. PARP-1 is a key sensor of DNA strand breaks and becomes automodified in response to DNA damage. PARP-1 activation occurs following recognition of single or double strand breaks by PARP-1's N-terminal zinc finger domains. A multi-domain allosteric activation pathway leads to conformational changes in the HD subdomain of the catalytic domain that promote increased catalytic activity and lead to PARP-1 automodification and recruitment of DNA damage response proteins. Small molecule inhibitors of PARP-1 catalytic domain activity are also the first compounds to be discovered which target tumour cells with deficiencies in homologous recombination via a synthetically lethal approach. PARP-1 inhibitors cause cytotoxicity by preventing PARP-1 from being released from sites of DNA damage, but the mechanistic basis of the wide differences in effectiveness between different compounds has yet to be definitively established. Therefore, the aims of the work described in this thesis are to further elucidate the changes that occur in the HD subdomain during catalytic domain activation, and to help establish how binding of different PARP inhibitors to the catalytic domain in solution leads to the formation of trapped PARP-1 lesions using NMR spectroscopy.
Supervisor: Neuhaus, David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: PARP-1 ; PARP inhibitors ; PARP inhibition ; DNA damage response ; ADP-ribose ; ADP-ribosylation ; NMR spectroscopy ; Biomolecular NMR