Ivan Ahel

DNA repair mechanisms and human disease

Our genome is constantly exposed to various types of DNA damage, both endogenous and exogenous. It has been estimated that the DNA in every cell of our body suffers thousands of DNA lesions per day, which, if left unattended, can lead to mutations and/or cell death. Our cells have evolved a variety of mechanisms to counteract deleterious effects of DNA damage, and if intact, these mechanisms are normally sufficient to sustain genome stability.

Poly(ADP-ribose) glycohydrolase bound to ADP-ribose.

Localisation of PARP1 to the sites of DNA damage in a living cell.

To date, a number of genetic diseases are known to be linked to defects in specific components of various DNA damage response pathways. Such diseases are extensively linked with cancer, neurodegeneration, immunodeficiency or developmental abnormalities.

Our laborabtory utilises biochemistry, structural biology, cell biology and animal models (mouse, fish and Drosophila) to study pathways and protein functions underlying genome stability, and which are regulated by a type of post-translational protein modification called ADP-ribosylation. ADP-ribosylation is performed by several families of enzymes including poly(ADP-ribose) polymerases (PARPs). Our research covers specific areas including the characterisation of novel DNA repair factors regulated by PARPs, understanding the regulation of how protein ADP-ribosylation is reversed, novel functions of PARP proteins beyond DNA repair, and the role of protein ADP-ribosylation in regulating oxidative stress and microbial pathogenesis. Our aim is to provide a mechanistic understanding of these processes as well as providing a platform for targeting them to develop ways of treating and preventing disease.

Relevant Publications

Gibbs-Seymour I., Fontana P., Rack J.G., Ahel I.
2016

Mol Cell 62(3): 432-442.

Rack J.G., Morra R., Barkauskaite E., Kraehenbuehl R., Ariza A., Qu Y., Ortmayer M., Leidecker O., Cameron D.R., Matic I., Peleg A.Y., Leys D., Traven A., Ahel I.
2015

Mol Cell 59(2): 309-320.

Barkauskaite E., Brassington A., Tan E.S., Warwicker J., Dunstan M.S., Banos B., Lafite P., Ahel M., Mitchison T.J., Ahel I.*, Leys D.*
2013

Nat Commun. 4: 2164.

*corresponding authors

Sharifi, R., Morra, R., Appel, C., Tallis, M., Chioza, B., Jankevicius, G., Simpson, M.A., Matic, I., Ozkan, E., Golia, B., Schellenberg, M.J., Weston, R., Williams, J.G., Rossi, M.N., Galehdari, H., A.H, Ahel, D., Williams, R.S., Ahel, I.
2013

EMBO J. 32: 1225-37.

Matic I., Ahel I., Hay R.T.
2012

Nat Methods 9(8): 771-772.

Slade, D., Dunstan, M.S., Barkauskaite, E., Weston, R., Lafite, P., Dixon, N., Ahel, M., Leys, D. and Ahel, I
2011

Nature 477: 616-620.

Chen D., Vollmar M., Rossi M.N., Phillips C., Kraehenbuehl R., Slade D., Mehrotra P.V., von Delft F., Crosthwaite S.K., Gileadi O., Denu J.M., Ahel I.
2011

J Biol Chem 286(15): 13261-71.

Mehrotra P.V., Ahel D., Ryan D.P., Weston R., Wiechens N., Kraehenbuehl R., Owen-Hughes T., Ahel I.
2011

Mol Cell. 41(1): 46-55.

Ahel, I.*, Ahel, D.*, Matsusaka, T., Clark, A.J., Pines, J., Boulton, S. and West, S.C
2008

Nature 451: 81-85.

*equal contribution

Ahel I., Rass U., El-Khamisy S.F., Katyal S., Clements P.M., McKinnon P.J., Caldecott K.W., West S.C.
2006

Nature 443(7112): 713-716.