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Regulation of genome stability and human disease

  • Full or part time
    Dr I Ahel
  • Application Deadline
    Friday, January 10, 2020
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

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 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 University fees, a tax free stipend of ~£17,009 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See View Website for full details and to apply.

References

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.
Bonfiglio, J.J., Fontana, P., Zhang, Q., Colby, T., Gibbs-Seymour, I., Atanassov, I., Bartlett, E.J., Zaja, R., Ahel, I.*, and Matic, I.* (2017) Serine ADP-ribosylation depends on HPF1. Mol Cell 65, 932-940. (*Corresponding authors)
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.

How good is research at University of Oxford in Biological Sciences?

FTE Category A staff submitted: 223.80

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