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.
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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.
2020
HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation.
Suskiewicz, M.J., Zobel, F., Ogden, T.E.H., Fontana, P., Ariza, A., Yang, J.C., Zhu, K., Bracken, L., Hawthorne, W.J., Ahel, D., Neuhaus, D. and Ahel, I.
Nature – 579(7800):598-602.
2016
The Toxin-Antitoxin System DarTG Catalyzes Reversible ADP-Ribosylation of DNA.
Jankevicius, G., Ariza, A., Ahel, M and, Ahel, I.
Molecular Cell – 64(6): 1109-1116.
2016
The Conserved Coronavirus Macrodomain Promotes Virulence and Suppresses the Innate Immune Response during Severe Acute Respiratory Syndrome Coronavirus Infection.
Fehr, A.R., Channappanavar, R., Jankevicius, G., Fett, C., Zhao, J., Athmer, J., Meyerholz, D.K., Ahel, I. and Perlman, S.
mBio. – 7(6): e01721-16.
2016
HPF1/C4orf27 Is a PARP-1-Interacting Protein that Regulates PARP-1 ADP-Ribosylation Activity.
Gibbs-Seymour, I., Fontana, P., Rack, J.G. and Ahel, I.
Molecular Cell – 62(3): 432-442.
2015
Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens.
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.and Ahel, I.
Molecular Cell – 59(2): 309-20.
2013
Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease.
Sharifi, R., Morra, R., Denise 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., Krahn, J., Wan, A., Trembath, R.C., Crosby, A.H., Ahel, D., Hay, R., Ladurner, A.G., Timinszky, G., Scott Williams, R. and Ahel, I.
EMBO J. – 32(9): 1225-37.
2011
The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase.
Slade, D., Dunstan, M.S., Barkauskaite, E., Weston, R., Lafite, P., Dixon, N., Ahel, M., Leys, D. and Ahel, I
Nature – 477(7366): 616-20.
2011
DNA repair factor APLF is a histone chaperone.
Mehrotra, P.V., Ahel, D., Ryan, D.P., Weston, R., Wiechens, N., Kraehenbuehl, R., Owen-Hughes, T. and Ahel, I.
Molecular Cell – 41(1): 46-55.
Ivan Ahel Elected as a Fellow of the Academy of Medical Sciences
May 2024
This honour recognises Prof Ivan Ahel’s leading contribution to the field of ADP-ribosylation and genome stability.
Two Dunn School groups awarded Wellcome Trust Discovery Awards
April 2024
Many congratulations to Professor Ivan Ahel and Professor Omer Dushek for securing these prestigious 8-year programme grants.
New study sheds light on the conservation of the Serine ADP-ribosylation pathway
July 2023
A new collaborative study demonstrates the conservation of HPF1 across all clades of the animal kingdom, and underlines the importance of serine ADP-ribosylation in DNA damage response signalling.
Dunn School postdoc starts lab at the University of Exeter
May 2023
Dr Johannes Rack starts his lab at the University of Exeter thanks to prestigious MRC Career Development Award.