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

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 act...

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Bibliographic Details
Published in:ACS chemical biology 2019-10, Vol.14 (10), p.2148-2154, Article acschembio.9b00570
Main Authors: Cornwell, Matthew J, Thomson, Graeme J, Coates, Julia, Belotserkovskaya, Rimma, Waddell, Ian D, Jackson, Stephen P, Galanty, Yaron
Format: Article
Language:English
Subjects:
Cell Line, Tumor
Fanconi Anemia - metabolism
Fanconi Anemia Complementation Group L Protein - antagonists & inhibitors
Fanconi Anemia Complementation Group L Protein - metabolism
High-Throughput Screening Assays
Humans
Letters
Small Molecule Libraries - pharmacology
Ubiquitin-Conjugating Enzymes - antagonists & inhibitors
Ubiquitin-Conjugating Enzymes - metabolism
Ubiquitination
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Summary: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.
ISSN:1554-8929
1554-8937
DOI:10.1021/acschembio.9b00570