Regulation of DNA Methylation Patterns by CK2-Mediated Phosphorylation of Dnmt3a

Deplus, Rachel; Blanchon, Loı̈c; Rajavelu, Arumugam; Boukaba, Abdel Halim; Defrance, Matthieu; Luciani, Judith; Rothé, Françoise; Dedeurwaerder, Sarah; Denis, Hélène; Brinkman, Arie B.; Simmer, Femke; Müller, Fabian; Bertin, Benjamin; Berdasco, María; Putmans, Pascale; Calonne, Emilie; Litchfield, David Dw; Launoit, Yvan de; Jurkowski, Tomasz P.; Stunnenberg, Hendrik Hg; Bock, Christoph; Sotiriou, Christos; Fraga, Mario F.; Esteller, Manel; Jeltsch, Albert; Fuks, François

doi:10.1016/j.celrep.2014.06.048

Cited by 70 publications

(54 citation statements)

References 42 publications

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“…Deplus et al showed that CK2 phosphorylates Ser386 and Ser389 located near the CK2 PWWP domain, which is the conserved Pro-Trp-Trp-Pro motif, and inhibits the ability of the PWWP domain to promote DNA methylation (25). As explained above, we found that d-flow significantly increased PKCf activation.…”

Section: Dnmt Phosphorylation and Methylationsupporting

confidence: 71%

“…AKT and PKC can phosphorylate DNMT1, and AKT1-mediated Ser143 DNMT1 phosphorylation stabilizes DNMT1 and decreases the ability of DNMT1 to associate with PCNA and UHRF1, which are involved in sustaining DNA methylation patterns through the recruitment of DNMT1 (29). Recently, Deplus et al investigated the role of casein kinase II (CK2) in regulating Dnmt3a activity (25). CK2 is a serine/threonine kinase, which is constitutively active and ubiquitously expressed in all mammalian tissue and cell types (30,90,123).…”

Section: Dnmt Phosphorylation and Methylationmentioning

confidence: 99%

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Disturbed Flow-Induced Endothelial Proatherogenic Signaling Via Regulating Post-Translational Modifications and Epigenetic Events

Heo

Berk

Abe

2016

Antioxidants & Redox Signaling

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Significance: Hemodynamic shear stress, the frictional force exerted onto the vascular endothelial cell (EC) surface, influences vascular EC functions. Atherosclerotic plaque formation in the endothelium is known to be site specific: disturbed blood flow (d-flow) formed at the lesser curvature of the aortic arch and branch points promotes plaque formation, and steady laminar flow (s-flow) at the greater curvature is atheroprotective. Recent Advances: Post-translational modifications (PTMs), including phosphorylation and SUMOylation, and epigenetic events, including DNA methylation and histone modifications, provide a new perspective on the pathogenesis of atherosclerosis, elucidating how gene expression is altered by d-flow. Activation of PKCf and p90RSK, SUMOylation of ERK5 and p53, and DNA hypermethylation are uniquely induced by d-flow, but not by s-flow. Critical Issues: Extensive cross talk has been observed among the phosphorylation, SUMOylation, acetylation, and methylation PTMs, as well as among epigenetic events along the cascade of d-flow-induced signaling, from the top (mechanosensory systems) to the bottom (epigenetic events). In addition, PKCf activation plays a role in regulating SUMOylation-related enzymes of PIAS4, p90RSK activation plays a role in regulating SUMOylation-related enzymes of Sentrin/SUMO-specific protease (SENP)2, and DNA methyltransferase SUMOylation may play a role in d-flow signaling. Future Directions: Although possible contributions of DNA events such as histone modification and the epigenetic and cytosolic events of PTMs in d-flow signaling have become clearer, determining the interplay of each PTM and epigenetic event will provide a new paradigm to elucidate the difference between d-flow and s-flow and lead to novel therapeutic interventions to inhibit plaque formation. Antioxid. Redox Signal. 25,[435][436][437][438][439][440][441][442][443][444][445][446][447][448][449][450]

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Section: Dnmt Phosphorylation and Methylationsupporting

confidence: 71%

Section: Dnmt Phosphorylation and Methylationmentioning

confidence: 99%

Disturbed Flow-Induced Endothelial Proatherogenic Signaling Via Regulating Post-Translational Modifications and Epigenetic Events

Heo

Berk

Abe

2016

Antioxidants & Redox Signaling

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“…Cell Line 4D-Nucleofector X KitLonzaCat# V4XC1012 Deposited Data Raw data (ChIP-seq and BLESS)This paperArrayExpress: E-MTAB-5817RAD51 and XRCC4 ChIP-seqAymard et al., 2014ArrayExpressE-MTAB-1241RNA polymerase II S2P ChIP-seqCohen et al., 2018ArrayExpressE-MTAB-6318MethylCap-seqDeplus et al., 2014GEO GSE26810 Experimental Models: Cell Lines DIvA cellIacovoni et al., 2010N/AU20S-ISceI GFP-RFP (NHEJ)Jacquet et al., 2016N/A3xFlag-Twin-strep-tagged SUPT7L K562Dalvai et al., 2015N/AU2OSN/AATCC HTB-96, RRID:CVCL_0042 Oligonucleotides HR-DSB1 for ChIP-qPCRFW GATTGGCTATGGGTGTGGACREV CATCCTTGCAAACCAGTCCTAymard et al., 2014N/AHR-DSB2 for ChIP-qPCRFW CCGCCAGAAAGTTTCCTAGAREV CTCACCCTTGCAGCACTTGAymard et al., 2014N/ANHEJ-DSB for ChIP-qPCRFW TGCCGGTCTCCTAGAAGTTGREV GCGCTTGATTTCCCTGAGTAymard et al., 2014N/AACTB for ChIP-qPCRFW AGCCGGGCTCTTGCCAATREV AGTTAGCGCCCAAAGGACCAThis paperN/ATAF12 for ChIP-qPCRFW GCTGAGACGAACGCTTCACTREV CCTTCGAACACTGACCCACTThis paperN/AsiRNA siSUPT7L-46 CUACUAGACCCAACAGAAA[dT] [dT] UUUCUGUUGGGUCUAGUAG[dT] [dT]This paperN/AsiRNA siSUPT7L-47 CUAUCACAGUUACAUGCUA[dT] [dT]UAGCAUGUAACUGUGAUAG[dT] [dT]This paperN/AsiRNA siKAT2B (PCAF) CUCUAAUCCUCACUCAUUU[dT] [dT]AAAUGAGUGAGGAUUAGAG[dT] [dT]This paperN/AsiRNA siKAT2A (GCN5) GCUACUACGUGACCCGGAA[dT] [dT]UUCCGGGUCACGUAGUAGC[dT] [dT]This paperN/A Recombinant DNA pX330-LMNAgRNA1Pauty et a...…”

Section: Methodsmentioning

confidence: 99%

Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

et al. 2018

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SummaryDouble-strand breaks (DSBs) are extremely detrimental DNA lesions that can lead to cancer-driving mutations and translocations. Non-homologous end joining (NHEJ) and homologous recombination (HR) represent the two main repair pathways operating in the context of chromatin to ensure genome stability. Despite extensive efforts, our knowledge of DSB-induced chromatin still remains fragmented. Here, we describe the distribution of 20 chromatin features at multiple DSBs spread throughout the human genome using ChIP-seq. We provide the most comprehensive picture of the chromatin landscape set up at DSBs and identify NHEJ- and HR-specific chromatin events. This study revealed the existence of a DSB-induced monoubiquitination-to-acetylation switch on histone H2B lysine 120, likely mediated by the SAGA complex, as well as higher-order signaling at HR-repaired DSBs whereby histone H1 is evicted while ubiquitin and 53BP1 accumulate over the entire γH2AX domains.

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“…HDAC inhibitors (HDACi), such as MS275 (entinostat) and SAHA (vorinostat), are able to maintain or restore the acetylation status of histone and non-histone targets and may thus have important therapeutic applications. Some of these inhibitors have already been used as antitumor agents, 5,6 showing significant activity against a variety of both hematological and solid tumors at relatively well-tolerated pharmacological doses. [7][8][9] Although little is known about the specific role of HDACs during hematopoiesis, altered HDAC activity has been directly linked with genesis of acute promyelocytic leukemia (APL) [10][11][12] and other types of leukemias.…”

Section: Introductionmentioning

confidence: 99%

ARHGEF3 controls HDACi-induced differentiation via RhoA-dependent pathways in acute myeloid leukemias

et al. 2015

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Altered expression and activity of histone deacetylases (HDACs) have been correlated with tumorigenesis. Inhibitors of HDACs (HDACi) induce acetylation of histone and non-histone proteins affecting gene expression, cell cycle progression, cell migration, terminal differentiation and cell death. Here, we analyzed the regulation of ARHGEF3, a RhoA-specific guanine nucleotide exchange factor, by the HDACi MS275 (entinostat). MS275 is a well-known benzamide-based HDACi, which induces differentiation of the monoblastic-like human histiocytic lymphoma cell line U937 to monocytes/macrophages. Incubation of U937 cells with MS275 resulted in an up regulation of ARHGEF3, followed by a significant enhancement of the marker of macrophage differentiation CD68. ARHGEF3 protein is primarily nuclear, but MS275 treatment rapidly induced its translocation into the cytoplasm. ARHGEF3 cytoplasmic localization is associated with activation of the RhoA/Rho-associated Kinase (ROCK) pathway. In addition to cytoskeletal rearrangements orchestrated by RhoA, we showed that ARHGEF3/RhoA-dependent signals involve activation of SAPK/JNK and then Elk1 transcription factor. Importantly, MS275-induced CD68 expression was blocked by exposure of U937 cells to exoenzyme C3 transferase and Y27632, inhibitors of Rho and ROCK respectively. Moreover, ARHGEF3 silencing prevented RhoA activation leading to a reduction in SAPK/JNK phosphorylation, Elk1 activation and CD68 expression, suggesting a crucial role for ARHGEF3 in myeloid differentiation. Taken together, our results demonstrate that ARHGEF3 modulates acute myeloid leukemia differentiation through activation of RhoA and pathways directly controlled by small GTPase family proteins. The finding that GEF protein modulation by HDAC inhibition impacts on cell differentiation may be important for understanding the antitumor mechanism(s) by which HDACi treatment stimulates differentiation in cancer.

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Regulation of DNA Methylation Patterns by CK2-Mediated Phosphorylation of Dnmt3a

Cited by 70 publications

References 42 publications

Disturbed Flow-Induced Endothelial Proatherogenic Signaling Via Regulating Post-Translational Modifications and Epigenetic Events

Disturbed Flow-Induced Endothelial Proatherogenic Signaling Via Regulating Post-Translational Modifications and Epigenetic Events

Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

ARHGEF3 controls HDACi-induced differentiation via RhoA-dependent pathways in acute myeloid leukemias

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