Post-translational modifications enable cells to rapidly respond to environmental and cellular challenges, including DNA damage. Our laboratory focuses on ADP-ribosylation, a dynamic posttranslational modification catalysed by the PARP family of enzymes, and its role in coordinating the DNA damage response. Through a combination of cell biology, biochemistry, and advanced live-cell imaging approaches, we investigate how ADP-ribosylation regulates DNA repair pathways and maintains genome stability.
PARP inhibitors have transformed the treatment of several cancers, including breast, ovarian, prostate, and pancreatic cancer, highlighting the clinical importance of this signaling pathway. By deciphering the molecular mechanisms underlying ADP-ribosylation-dependent DNA repair, we aim to identify novel therapeutic vulnerabilities that can be exploited to develop more effective and targeted cancer therapies.
Current research projects
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A role for ADPr-Ub in the DNA damage response and as a modulator of the PARPi response
The complexity of ADP-ribose signalling has recently been extended by the identification of ADP-ribosyl-ubiquitin, where ubiquitin is added directly onto ADP-ribose creating a hybrid modification. We aim to identify the role of ADPr-Ub in DNA repair and decipher the role of different factors in the signalling pathway. Armed with the knowledge that changes to ADP-ribose signalling can regulate the PARP inhibitor response, this project aims to determine how ADPr-Ub regulates the cellular response to PARPi, and to identify potential targetable vulnerabilities for the development of novel cancer therapies.
People
Available for Student Supervision
Selected publications
Chatrin, C., Zhu, K., Simmons, M. D. R., Maginn, L., Schützenhofer, K., Lu, Y., Đukić, N., Wijngaarden, S., Kloet, M. S., Kliza, K. W., Heden van Noort, G. J. v. d., Filippov, D. V., Ahel, D., Smith, R.*, & Ahel, I*. (†Co-lead author, *Co-corresponding) (2026). Specificity and recognition of the ADP-ribosyl-ubiquitin modification in the DNA damage response. PLOS Biology, 24(4), e3003747. https://doi.org/10.1371/journal.pbio.3003747
Schützenhofer, K., Laker, E., Tsang, K., Baretić, D., Suskiewicz, M. J., Zobel, F. F. H., Simmons, M. D. R., Chatrin, C., Smith, R.*, & Ahel, I*. (†Co-lead author, *Co-corresponding) (2026). PARP1-specific inhibitor displays PARP1-detrapping activity. Cell Reports, 45(5). https://doi.org/10.1016/j.celrep.2026.117350
Zentout, S., Imburchia, V., Chapuis, C., Duma, L., Schützenhofer, K., Prokhorova, E., Ahel, I., Smith, R.*, & Huet, S*. (*Co-corresponding) (2024). Histone ADP-ribosylation promotes resistance to PARP inhibitors by facilitating PARP1 release from DNA lesions. Proceedings of the National Academy of Sciences, 121(25), e2322689121. https://doi.org/10.1073/pnas.2322689121
Pinto Jurado, E.†, Smith, R.†*, Bigot, N., Chapuis, C., Timinszky, G.*, & Huet, S.* (†Co-lead author, *Co-corresponding) (2024). The recruitment of ACF1 and SMARCA5 to DNA lesions relies on ADP-ribosylation dependent chromatin unfolding. Molecular Biology of the Cell, 35(3), br7. https://doi.org/10.1091/mbc.E23-07-0281
Smith, R.†*, Zentout, S.†, Rother, M., Bigot, N., Chapuis, C., Mihuț, A., Zobel, F. F., Ahel, I., van Attikum, H., Timinszky, G., & Huet, S*. (†Co-lead author, *Co-corresponding) (2023). HPF1-dependent histone ADP-ribosylation triggers chromatin relaxation to promote the recruitment of repair factors at sites of DNA damage. Nature Structural & Molecular Biology. https://doi.org/10.1038/s41594-023-00977-x
Juhász, S.†, Smith, R.†, Schauer, T., Spekhardt, D., Mamar, H., Zentout, S., Chapuis, C., Huet, S., & Timinszky, G. (†Co-lead author) (2020). The chromatin remodeler ALC1 underlies resistance to PARP inhibitor treatment. Science Advances, 6(51), eabb8626. https://doi.org/10.1126/sciadv.abb8626
ORCID profile: https://orcid.org/0000-0002-1658-5635
Google Scholar profile: https://scholar.google.com/citations?user=KE4Mc7QAAAAJ&hl=en
Related news
New funding to advance DNA repair and cancer treatment research at SVI
SVI is welcoming DNA damage and repair researcher Dr Rebecca Smith, thanks to funding from the Cancer Council Victoria’s Cancer Research Fellowship Victoria Program, announced today.