Small-Molecule Inhibition of UBE2T/FANCL-Mediated Ubiquitylation in the Fanconi Anemia Pathway.

Matthew J Cornwell, Graeme J Thomson, Julia Coates, Rimma Belotserkovskaya, Ian D Waddell, Stephen P Jackson, Yaron Galanty

ACS chemical biology 2019 Oct 18

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The 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.

Citation

Matthew J Cornwell, Graeme J Thomson, Julia Coates, Rimma Belotserkovskaya, Ian D Waddell, Stephen P Jackson, Yaron Galanty. Small-Molecule Inhibition of UBE2T/FANCL-Mediated Ubiquitylation in the Fanconi Anemia Pathway. ACS chemical biology. 2019 Oct 18;14(10):2148-2154