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
MetadataShow full item record
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
- UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation.
- Authors: Machida YJ, Machida Y, Chen Y, Gurtan AM, Kupfer GM, D'Andrea AD, Dutta A
- Issue date: 2006 Aug
- Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia.
- Authors: Rickman KA, Lach FP, Abhyankar A, Donovan FX, Sanborn EM, Kennedy JA, Sougnez C, Gabriel SB, Elemento O, Chandrasekharappa SC, Schindler D, Auerbach AD, Smogorzewska A
- Issue date: 2015 Jul 7
- Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI.
- Authors: Alpi AF, Pace PE, Babu MM, Patel KJ
- Issue date: 2008 Dec 26
- The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL.
- Authors: Miles JA, Frost MG, Carroll E, Rowe ML, Howard MJ, Sidhu A, Chaugule VK, Alpi AF, Walden H
- Issue date: 2015 Aug 21
- Allosteric mechanism for site-specific ubiquitination of FANCD2.
- Authors: Chaugule VK, Arkinson C, Rennie ML, Kämäräinen O, Toth R, Walden H
- Issue date: 2020 Mar