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 cancer avoidance. 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 and cancer.
We are particularly interested in a family of proteins called SNF2 ATPases. SNF2 ATPases are multidomain proteins, characterized by the presence of a specific domain which 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. More importantly, a large number of SNF2 helicases have directly been linked to cancer and human disease. This underlines the biological relevance of this family, suggesting that studying SNF2 ATPases may provide important insights into cancer and the relevant biological mechanisms associated with the maintenance of genome integrity.
The recent focus in our laboratory has been on novel SNF2 family members. The student project will focus on the characterisation of one these factors to uncover its precise role in the maintenance of genome stability. The project will also examine the link between SNF2 ATPases and human disease. It will include a detailed study of a candidate protein and involve a combination of different techniques, including cell biology, protein biochemistry, bioinformatics and structural biology.
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.