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Title: Structural and functional analysis of serine-ADP-ribosylation
Author: Fontana, Pietro
ISNI:       0000 0004 7653 7859
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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ADP-ribosylation is a protein post-translational modification involved in several biological pathways, including the DNA damage response. PARP1, one of the primary sensors of DNA breaks, and the main enzyme responsible for ADP-ribosylation has been the subject of study for several years. Despite the revelations from previous studies, we still lack a full understanding behind PARP1 regulation and activity. In this thesis, I will describe the identification and characterisation of a novel interactor/regulator of the PARP1 cycle, which we named Histone Parylation Factor 1 (HPF1), with particular emphasis of its role in DNA repair. In the second chapter, I will show a structural and biochemical characterisation of HPF1 and the discovery of HPF1 as a specificity factor inducing a novel post-translational modification named serine-ADP-ribosylation. In the third chapter, I will show that serine-ADP-ribosylation induced by HPF1 is a reversible post-translational modification. Further, I will show that the only human enzyme able to reverse serine-ADP-ribosylation is the previously poorly characterised glycohydrolase ARH3, and show an overall biochemical characterisation of ARH3. Finally, in the fourth and last experimental chapter, I will show that serine-ADP-ribosylation is a post-translational modification present also in the model organism Drosophila melanogaster. However, I'll show that in Drosophila the enzyme responsible for its removal is DmParg, as Drosophila do not possess an ARH3 homolog. Finally, I will show a biochemical characterisation of DmParg and preliminary data for its structural characterisation.
Supervisor: Ahel, Ivan Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available