Small Molecule Inhibition of UBE2T/FANCL-mediated Ubiquitylation in the Fanconi Anemia Pathway
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Peer-reviewed
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Article
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Authors
Cornwell, Matthew J
Thomson, Graeme J
Coates, Julia
Belotserkovskaya, Rimma
Waddell, Ian D
Abstract
The Fanconi anemia pathway orchestrates the repair of DNA inter-strand crosslinks and stalled replication forks. A key step in this pathway is UBE2T and FANCL dependent monoubiquitylation of the FANCD2-FANCI complex. The Fanconi anemia pathway represents an attractive therapeutic target because activation of this pathway has been linked to chemotherapy resistance in several cancers. However, very few selective inhibitors of ubiquitin conjugation pathways are known to date. By using a high-throughput screen compatible assay, we have identified a small molecule inhibitor of UBE2T/FANCL-mediated FANCD2 monoubiquitylation that sensitizes cells to the DNA cross-linking agent, carboplatin.
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Keywords
Cell Line, Tumor, Fanconi Anemia, Fanconi Anemia Complementation Group L Protein, High-Throughput Screening Assays, Humans, Small Molecule Libraries, Ubiquitin-Conjugating Enzymes, Ubiquitination
Journal Title
ACS Chemical Biology
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Journal ISSN
1554-8929
1554-8937
1554-8937
Volume Title
14
Publisher
American Chemical Society (ACS)
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Sponsorship
Cancer Research UK (18796)
Wellcome Trust (206388/Z/17/Z)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
Wellcome Trust (206388/Z/17/Z)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
M.J.C was funded through the Cambridge PhD Training Programme in Chemical Biology and Molecular Medicine. Y.G is funded by Cancer Research UK, C6/A18796 and a Wellcome Trust Investigator Award to S.P.J. 206388/Z/17/Z. Research in the Jackson lab is funded by CRUK (C6/A18796) and the Wellcome Trust (206388/Z/17/Z), with core infrastructure funding from the Wellcome Trust (203144) and CRUK (C6946/A24843). Work in the CRUK Manchester Institute Drug Discovery Unit was funded by CRUK (Grant numbers C480/A1141 and C309/A8274).