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

[Image: see text] 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 t...

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Autores principales: Cornwell, Matthew J., Thomson, Graeme J., Coates, Julia, Belotserkovskaya, Rimma, Waddell, Ian D., Jackson, Stephen P., Galanty, Yaron
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804243/
https://www.ncbi.nlm.nih.gov/pubmed/31525021
http://dx.doi.org/10.1021/acschembio.9b00570
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author Cornwell, Matthew J.
Thomson, Graeme J.
Coates, Julia
Belotserkovskaya, Rimma
Waddell, Ian D.
Jackson, Stephen P.
Galanty, Yaron
author_facet Cornwell, Matthew J.
Thomson, Graeme J.
Coates, Julia
Belotserkovskaya, Rimma
Waddell, Ian D.
Jackson, Stephen P.
Galanty, Yaron
author_sort Cornwell, Matthew J.
collection PubMed
description [Image: see text] 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.
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spelling pubmed-68042432019-10-23 Small-Molecule Inhibition of UBE2T/FANCL-Mediated Ubiquitylation in the Fanconi Anemia Pathway Cornwell, Matthew J. Thomson, Graeme J. Coates, Julia Belotserkovskaya, Rimma Waddell, Ian D. Jackson, Stephen P. Galanty, Yaron ACS Chem Biol [Image: see text] 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. American Chemical Society 2019-09-16 2019-10-18 /pmc/articles/PMC6804243/ /pubmed/31525021 http://dx.doi.org/10.1021/acschembio.9b00570 Text en Copyright © 2019 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Cornwell, Matthew J.
Thomson, Graeme J.
Coates, Julia
Belotserkovskaya, Rimma
Waddell, Ian D.
Jackson, Stephen P.
Galanty, Yaron
Small-Molecule Inhibition of UBE2T/FANCL-Mediated Ubiquitylation in the Fanconi Anemia Pathway
title Small-Molecule Inhibition of UBE2T/FANCL-Mediated Ubiquitylation in the Fanconi Anemia Pathway
title_full Small-Molecule Inhibition of UBE2T/FANCL-Mediated Ubiquitylation in the Fanconi Anemia Pathway
title_fullStr Small-Molecule Inhibition of UBE2T/FANCL-Mediated Ubiquitylation in the Fanconi Anemia Pathway
title_full_unstemmed Small-Molecule Inhibition of UBE2T/FANCL-Mediated Ubiquitylation in the Fanconi Anemia Pathway
title_short Small-Molecule Inhibition of UBE2T/FANCL-Mediated Ubiquitylation in the Fanconi Anemia Pathway
title_sort small-molecule inhibition of ube2t/fancl-mediated ubiquitylation in the fanconi anemia pathway
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804243/
https://www.ncbi.nlm.nih.gov/pubmed/31525021
http://dx.doi.org/10.1021/acschembio.9b00570
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