TY - JOUR

T1 - DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias

AU - Boulanger, Mathias

AU - Aqrouq, Mays

AU - Tempé, Denis

AU - Kifagi, Chamseddine

AU - Ristic, Marko

AU - Akl, Dana

AU - Hallal, Rawan

AU - Carusi, Aude

AU - Gabellier, Ludovic

AU - de Toledo, Marion

AU - Sigurdsson, Jon-Otti

AU - Kaoma, Tony

AU - Andrieu-Soler, Charlotte

AU - Forné, Thierry

AU - Soler, Eric

AU - Hicheri, Yosr

AU - Gueret, Elise

AU - Vallar, Laurent

AU - Olsen, Jesper V.

AU - Cartron, Guillaume

AU - Piechaczyk, Marc

AU - Bossis, Guillaume

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

U2 - 10.1093/nar/gkad581

DO - 10.1093/nar/gkad581

M3 - Journal article

C2 - 37462077

VL - 51

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 16

ER -