Small-molecule inhibition of UBE2T/FANCL-mediated ubiquitylation in the Fanconi Anemia pathway
Thomson, Graeme J
Waddell, Ian D
AffiliationThe Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry , University of Cambridge , Cambridge CB2 1QN , United Kingdom
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AbstractThe Fanconi anemia pathway orchestrates the repair of DNA interstrand cross-links 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, to date, very few selective inhibitors of ubiquitin conjugation pathways are known. 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.
CitationCornwell MJ, Thomson GJ, Coates J, Belotserkovskaya R, Waddell ID, Jackson SP, et al. Small-molecule inhibition of UBE2T/FANCL-mediated ubiquitylation in the Fanconi Anemia pathway. ACS Chem Biol. 2019 Sep 23.
JournalACS Chemical Biology
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