About the Project
PARP1 is the most active PARP enzyme in human cells and it is critical for the regulation of nuclear processes such as DNA damage repair, transcription, maintenance of chromatin structure, replication and mitosis. In our laboratory we recently identified a previously uncharacterised protein as an interactor of PARP1. We have called this novel chromatin factor HPF1 (for histone PARylation factor 1) and showed that HPF1 allows PARP1 to specifically ADP-ribosylate serine residues in histones and many other proteins important for the maintenance of genome stability. Additionally, we uncovered that ARH3 enzyme act as a specific hydrolase that reverses serine ADP-ribosylation in cells. The aim of the PhD project will be to elucidate the exact molecular and physiological functions of HPF1, ARH3 and their target proteins in regulation of genome stability. Our laboratory covers a large variety of techniques that will enable us to efficiently study this protein on different levels (protein biochemistry, cell biology, mouse and Drosophila melanogaster genetic models, bioinformatics and structural biology), and it will possible to tailor the experimental approach according to the student’s experience and preferences.
Bilokapic, S., Suskiewicz, M.J., Ahel, I., and Halic, M. (2020) Bridging of DNA breaks activates PARP2-HPF1 to modify chromatin. Nature 585(7826):609-613.
Palazzo, L., Leidecker, O., Prokhorova, E., Dauben, H., Matic, I., and Ahel, I. (2018) Serine is the major residue for ADP-ribosylation upon DNA damage. Elife Feb 26;7. pii: e34334.
Fontana, P., Bonfiglio, J.J., Palazzo, .L, Bartlett, E., Matic, I., and Ahel, I. (2017) Serine ADP-ribosylation reversal by the hydrolase ARH3. Elife 6. pii: e28533.
Gibbs-Seymour, I., Fontana, P., Rack, J.G., and Ahel, I. (2016) HPF1/C4orf27 Is a PARP-1-Interacting Protein that Regulates PARP-1 ADP-Ribosylation Activity. Mol Cell 62, 432-42.
Barkauskaite, E., Jankevicius, G., and Ahel, I. (2015) Structures and Mechanisms of Enzymes Employed in the Synthesis and Degradation of PARP-Dependent Protein ADP-Ribosylation. Mol Cell 58, 935-46.
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