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Regulation of genome stability and human disease


   Sir William Dunn School of Pathology

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  Dr I Ahel  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

Oxford United Kingdom Biochemistry Cancer Biology Cell Biology Genetics Molecular Biology Pathology Structural Biology

About the Project

Poly(ADP-ribose) polymerases (PARPs) are the major family of enzymes that synthesize an abundant posttranslational protein modification called ADP-ribosylation. Through their ability to modify different target proteins and to respond to variety of stimuli, PARPs control genome stability, cell differentiation, metabolism and immune responses. Inherited defects in the protein components of the pathways regulated by PARPs often cause disease in humans such as cancer, immunodeficiencies, neurodegeneration and developmental syndromes. In recent years it has become apparent that using specific drugs to inhibit or modulate protein ADP-ribosylation can be very effective in disease treatment (for example breast, ovarian, pancreatic and prostate cancer). Thus, furthering our knowledge of the protein factors and pathways regulated by PARPs provides a basis for the development of new therapies.

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. 


Funding Notes

4 Year DPhil Prize Studentships cover full University fees, a tax free enhanced stipend of ~£17,609 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See https://www.path.ox.ac.uk/content/prospective-graduate-students for full details and to apply.

References

1. Prokhorova, E., Zobel, F., Smith, R., Zentout, S., Gibbs-Seymour, I., Schützenhofer, K., Peters, A., Groslambert, J., Zorzini, V., Agnew, T., Brognard, J., Nielsen, M.L., Ahel, D., Huet, S., Suskiewicz, M.J., and Ahel, I. (2021) Serine-linked PARP1 auto-modification controls PARP inhibitor response. Nature Commun 12, 4055.
2. Suskiewicz, M.J., Zobel, F., Ogden, T.E., Fontana, P., Ariza, A., Yang, J., Zhu, K., Bracken, L., Hawthorne, W.J., Ahel, D., Neuhaus, D., and Ahel, I. (2020) HPF1 completes the PARP active site for DNA-damage induced ADP-ribosylation. Nature 579, 598-602.
3. Bilokapic, S., Suskiewicz, M.J., Ahel, I., and Halic, M. (2020) Bridging of DNA breaks activates PARP2-HPF1 to modify chromatin. Nature 585, 609-613.
4. 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.
5. 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.
6. 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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