PhD project

Supervisors: Dragana Ahel and Ivan Ahel

The maintenance of complete and undamaged genome is critical for survival. However, DNA is a fragile structure susceptible to DNA damage. It is continually exposed to assaults from the endogenous and exogenous sources, which challenge the integrity of genetic information. To cope with DNA damage, cells rely on various activities, which support genome stability and play major roles in avoiding pathological outcomes.

The goal of our research is to elucidate the fundamental mechanisms by which cells inspect and repair the genome, and explore the link of these mechanisms with human disease. Our previous efforts focused on a family of proteins called SNF2 ATPases. SNF2 ATPases are modular proteins, characterised by the presence of a specific domain that enables them to translocate along DNA. Interestingly, SNF2 ATPases play roles in a number of nuclear functions tightly associated with the maintenance of genome stability, such as chromatin remodelling, transcription, DNA replication, DNA repair and recombination. In recent years our research also extended beyond SNF2 ATPase family, and is largely focused on poorly characterised proteins with direct links to human disease, including cancer, viral infection and neurodegeneration.

The student project will involve a detailed study of a candidate protein with the aim of uncovering a mechanistic basis of their role in human pathology. Our laboratory has previously been successful in using a combination of cell biology, genomics, protein biochemistry, bioinformatics and structural biology, to address pertinent biological questions. The project will therefore be suitable for students with different background experiences, and provide opportunities for those whishing to expand their methodological skillset.

Keywords:

• Biochemistry, Cancer, Cell Biology, Molecular Biology, Pathology, Structural Biology, Virology

Publications:

• Carnie CJ, Armstrong L, Sebesta M, Ariza A, Wang X, Graham E, Zhu K, Ahel D. (2023) ERCC6L2 mitigates replication stress and promotes centromere stability. Cell Rep. 42(4):112329.
• Zhu K, Suskiewicz MJ, Hloušek-Kasun A, Meudal H, Mikoč A, Aucagne V, Ahel D, Ahel I. (2022) DELTEX E3 ligases ubiquitylate ADP-ribosyl modification on protein substrates. Sci Adv. 7;8(40).
• Sebesta, M., Cooper, C.D.O., Ariza, A., Carnie, C.J., Ahel, D. (2017) Structural insights into the function of ZRANB3 in replication stress response. Nat Commun 8, 15847.
• Weston, R., Peteers, H., and Ahel, D. (2012) ZRANB3 is a structure-specific ATP-dependent endonuclease involved in replication stress response. Genes Dev 26, 1558-72.
• Ahel, D., Horejsí, Z., Wiechens, N., Polo, S.E., Garcia-Wilson, E., Ahel, I., Flynn, H., Skehel, M., West, S.C., Jackson, S.P., Owen-Hughes, T., Boulton, S.J. (2009) Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science 325, 1240-1243.
• Ahel, I.*, Ahel, D.*, Matsusaka, T., Clark, A.J., Pines, J., Boulton, S., and West, S.C. (2008) Poly(ADPribose)-binding zinc finger motifs in DNA repair/checkpoint proteins. Nature 451, 81-85. (*equal contribution)
• Flaus, A., Martin, D.M., Barton, G.J., Owen-Hughes, T. (2006) Identification of multiple distinct Snf2 subfamilies with conserved structural motifs. Nucleic Acids Res. 34, 2887-905.