The destructive force of UV radiation on DNA molecules is only fully visible, when repair mechanisms fail: patients with the rare genetic disease Xeroderma pigmentosum – also known as “Moon children’ - develop inflammations upon exposure to only small amounts of sunlight, rough-surfaced growths and eventually skin cancer occurs often in early age. The severe condition is caused by mutations in the genes for the nucleotide excision repair (NER) pathway – the only known mechanism that deals with UV-induced DNA damage in human cells. Although first described in 1874, Xeroderma pigmentosum to date lacks any curative treatment.
Led by Joanna Loizou, Principal Investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, and together with collaborators from the Medical University of Vienna and the IRB Barcelona, the scientists at CeMM found in their most recent publication that the FDA-approved diabetes drug acetohexamide significantly improves the resilience of NER deficient cells against UV radiation in vitro. Above that, the study published in Molecular Cell (DOI: 10.1016/j.molcel.2017.10.021) identified the responsible molecular mode of action – a hitherto unknown, NER-independent repair mechanism for UV-induced DNA damage. The study has not tested the use of acetohexamide in Xeroderma pigmentosum patients.
For their study, the scientists of Loizou’s team developed a special chemical screening approach for compounds that would allow Xeroderma pigmentosum-disease cells to survival UV treatment better. Using the CLOUD (Cemm Library of Unique Drugs), this approach led to the identification of acetohexamide: By treating Xeroderma pigmentosum-disease cells with the diabetes drug, these cells could now repair UV-induced DNA damage more efficiently. A multitude of subsequent experiments eventually led to the elucidation of the underlying molecular mechanism: acetohexamide leads to the degradation of the DNA repair enzyme MUTYH, triggering an hitherto unknown NER-independent mechanism for removing UV-induced DNA damage.
Abdelghani Mazouzi, Federica Battistini, Sarah C. Moser, Joana Ferreira da Silva, Marc Wiedner, Michel Owusu, Charles-Hugues Lardeau, Anna Ringler, Beatrix Weil, Jürgen Neesen, Modesto Orozco, Stefan Kubicek and Joanna I. Loizou. Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH. Molecular Cell, November 16, 2017. DOI: 10.1016/j.molcel.2017.10.021
The study was supported by the Austrian Academy of Sciences, the European Commission, the Austrian Science Fund, the Austrian Federal Ministry of Science, Research and Economy, the National Foundation for Research, Technology, and Development, the Spanish Ministry of Science the Catalan Government, the Instituto de Salud Carlos III-Instituto Nacional de Bioinformática, and the European Research Council ERC.
Mag. Wolfgang Däuble
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