Small Molecule Inhibition of UBE2T/FANCL-mediated Ubiquitylation in the Fanconi Anemia Pathway
Authors
Cornwell, Matthew J
Thomson, Graeme J
Coates, Julia
Belotserkovskaya, Rimma
Waddell, Ian D
Journal Title
ACS Chemical Biology
ISSN
1554-8929
Publisher
American Chemical Society (ACS)
Volume
14
Issue
10
Pages
2148-2154
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Cornwell, M. J., Thomson, G. J., Coates, J., Belotserkovskaya, R., Waddell, I. D., Jackson, S., & Galanty, Y. (2019). Small Molecule Inhibition of UBE2T/FANCL-mediated Ubiquitylation in the Fanconi Anemia Pathway. ACS Chemical Biology, 14 (10), 2148-2154. https://doi.org/10.1021/acschembio.9b00570
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.
Sponsorship
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).
Funder references
Cancer Research UK (A18796)
Wellcome Trust (206388/Z/17/Z)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1021/acschembio.9b00570
This record's URL: https://www.repository.cam.ac.uk/handle/1810/296973
Rights
Attribution 4.0 International (CC BY)
Licence URL: http://creativecommons.org/licenses/by/4.0/