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DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias

Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drug...

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Autores principales: Boulanger, Mathias, Aqrouq, Mays, Tempé, Denis, Kifagi, Chamseddine, Ristic, Marko, Akl, Dana, Hallal, Rawan, Carusi, Aude, Gabellier, Ludovic, de Toledo, Marion, Sigurdsson, Jon-Otti, Kaoma, Tony, Andrieu-Soler, Charlotte, Forné, Thierry, Soler, Eric, Hicheri, Yosr, Gueret, Elise, Vallar, Laurent, Olsen, Jesper V, Cartron, Guillaume, Piechaczyk, Marc, Bossis, Guillaume
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10484680/
https://www.ncbi.nlm.nih.gov/pubmed/37462077
http://dx.doi.org/10.1093/nar/gkad581
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author Boulanger, Mathias
Aqrouq, Mays
Tempé, Denis
Kifagi, Chamseddine
Ristic, Marko
Akl, Dana
Hallal, Rawan
Carusi, Aude
Gabellier, Ludovic
de Toledo, Marion
Sigurdsson, Jon-Otti
Kaoma, Tony
Andrieu-Soler, Charlotte
Forné, Thierry
Soler, Eric
Hicheri, Yosr
Gueret, Elise
Vallar, Laurent
Olsen, Jesper V
Cartron, Guillaume
Piechaczyk, Marc
Bossis, Guillaume
author_facet Boulanger, Mathias
Aqrouq, Mays
Tempé, Denis
Kifagi, Chamseddine
Ristic, Marko
Akl, Dana
Hallal, Rawan
Carusi, Aude
Gabellier, Ludovic
de Toledo, Marion
Sigurdsson, Jon-Otti
Kaoma, Tony
Andrieu-Soler, Charlotte
Forné, Thierry
Soler, Eric
Hicheri, Yosr
Gueret, Elise
Vallar, Laurent
Olsen, Jesper V
Cartron, Guillaume
Piechaczyk, Marc
Bossis, Guillaume
author_sort Boulanger, Mathias
collection PubMed
description Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces rapid (3 h) and broad transcriptional changes in AML cells. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, in particular at active promoters and enhancers. Surprisingly, inhibition of SUMOylation with ML-792 (SUMO E1 inhibitor), dampens DNR-induced transcriptional reprogramming. Quantitative proteomics shows that the proteins deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. DNR leads to a reconfiguration of chromatin loops engaging CTCF- and SUMO-bound NFKB2 promoter with a distal cis-regulatory region and inhibition of SUMOylation with ML-792 prevents these changes.
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spelling pubmed-104846802023-09-08 DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias Boulanger, Mathias Aqrouq, Mays Tempé, Denis Kifagi, Chamseddine Ristic, Marko Akl, Dana Hallal, Rawan Carusi, Aude Gabellier, Ludovic de Toledo, Marion Sigurdsson, Jon-Otti Kaoma, Tony Andrieu-Soler, Charlotte Forné, Thierry Soler, Eric Hicheri, Yosr Gueret, Elise Vallar, Laurent Olsen, Jesper V Cartron, Guillaume Piechaczyk, Marc Bossis, Guillaume Nucleic Acids Res Gene regulation, Chromatin and Epigenetics Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces rapid (3 h) and broad transcriptional changes in AML cells. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, in particular at active promoters and enhancers. Surprisingly, inhibition of SUMOylation with ML-792 (SUMO E1 inhibitor), dampens DNR-induced transcriptional reprogramming. Quantitative proteomics shows that the proteins deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. DNR leads to a reconfiguration of chromatin loops engaging CTCF- and SUMO-bound NFKB2 promoter with a distal cis-regulatory region and inhibition of SUMOylation with ML-792 prevents these changes. Oxford University Press 2023-07-18 /pmc/articles/PMC10484680/ /pubmed/37462077 http://dx.doi.org/10.1093/nar/gkad581 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Gene regulation, Chromatin and Epigenetics
Boulanger, Mathias
Aqrouq, Mays
Tempé, Denis
Kifagi, Chamseddine
Ristic, Marko
Akl, Dana
Hallal, Rawan
Carusi, Aude
Gabellier, Ludovic
de Toledo, Marion
Sigurdsson, Jon-Otti
Kaoma, Tony
Andrieu-Soler, Charlotte
Forné, Thierry
Soler, Eric
Hicheri, Yosr
Gueret, Elise
Vallar, Laurent
Olsen, Jesper V
Cartron, Guillaume
Piechaczyk, Marc
Bossis, Guillaume
DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias
title DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias
title_full DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias
title_fullStr DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias
title_full_unstemmed DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias
title_short DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias
title_sort desumoylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias
topic Gene regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10484680/
https://www.ncbi.nlm.nih.gov/pubmed/37462077
http://dx.doi.org/10.1093/nar/gkad581
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