Publications by authors named "Claude Sardet"

41 Publications

Regulation of RAD51 at the Transcriptional and Functional Levels: What Prospects for Cancer Therapy?

Cancers (Basel) 2021 Jun 11;13(12). Epub 2021 Jun 11.

IRCM, Institut de Recherche en Cancérologie de Montpellier U1194 INSERM, Université de Montpellier, 34090 Montpellier, France.

The RAD51 recombinase is a critical effector of Homologous Recombination (HR), which is an essential DNA repair mechanism for double-strand breaks. The RAD51 protein is recruited onto the DNA break by BRCA2 and forms homopolymeric filaments that invade the homologous chromatid and use it as a template for repair. RAD51 filaments are detectable by immunofluorescence as distinct foci in the cell nucleus, and their presence is a read out of HR proficiency. RAD51 is an essential gene, protecting cells from genetic instability. Its expression is low and tightly regulated in normal cells and, contrastingly, elevated in a large fraction of cancers, where its level of expression and activity have been linked with sensitivity to genotoxic treatment. In particular, BRCA-deficient tumors show reduced or obliterated RAD51 foci formation and increased sensitivity to platinum salt or PARP inhibitors. However, resistance to treatment sets in rapidly and is frequently based on a complete or partial restoration of RAD51 foci formation. Consequently, RAD51 could be a highly valuable therapeutic target. Here, we review the multiple levels of regulation that impact the transcription of the RAD51 gene, as well as the post-translational modifications that determine its expression level, recruitment on DNA damage sites and the efficient formation of homofilaments. Some of these regulation levels may be targeted and their impact on cancer cell survival discussed.
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http://dx.doi.org/10.3390/cancers13122930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230762PMC
June 2021

Cerpegin-derived furo[3,4-c]pyridine-3,4(1H,5H)-diones enhance cellular response to interferons by de novo pyrimidine biosynthesis inhibition.

Eur J Med Chem 2020 Jan 6;186:111855. Epub 2019 Nov 6.

Chimie et Biologie, Modélisation et Immunologie pour la Thérapie (CBMIT), Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, CNRS UMR8601, Paris, France. Electronic address:

There is an increasing interest in the field of cancer therapy for small compounds targeting pyrimidine biosynthesis, and in particular dihydroorotate dehydrogenase (DHODH), the fourth enzyme of this metabolic pathway. Three available DHODH structures, featuring three different known inhibitors, were used as templates to screen in silico an original chemical library from Erevan University. This process led to the identification of P1788, a compound chemically related to the alkaloid cerpegin, as a new class of pyrimidine biosynthesis inhibitors. In line with previous reports, we investigated the effect of P1788 on the cellular innate immune response. Here we show that pyrimidine depletion by P1788 amplifies cellular response to both type-I and type II interferons, but also induces DNA damage as assessed by γH2AX staining. Moreover, the addition of inhibitors of the DNA damage response led to the suppression of the P1788 stimulatory effects on the interferon pathway. This demonstrates that components of the DNA damage response are bridging the inhibition of pyrimidine biosynthesis by P1788 to the interferon signaling pathway. Altogether, these results provide new insights on the mode of action of novel pyrimidine biosynthesis inhibitors and their development for cancer therapies.
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http://dx.doi.org/10.1016/j.ejmech.2019.111855DOI Listing
January 2020

Distinct oncogenes drive different genome and epigenome alterations in human mammary epithelial cells.

Int J Cancer 2019 09 10;145(5):1299-1311. Epub 2019 Jun 10.

IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Montpellier, France.

Molecular subtypes of breast cancer are defined on the basis of gene expression and genomic/epigenetic pattern differences. Different subtypes are thought to originate from distinct cell lineages, but the early activation of an oncogene could also play a role. It is difficult to discriminate the respective inputs of oncogene activation or cell type of origin. In this work, we wished to determine whether activation of distinct oncogenic pathways in human mammary epithelial cells (HMEC) could lead to different patterns of genetic and epigenetic changes. To this aim, we transduced shp53 immortalized HMECs in parallel with the CCNE1, WNT1 and RASv12 oncogenes which activate distinct oncogenic pathways and characterized them at sequential stages of transformation for changes in their genetic and epigenetic profiles. We show that initial activation of CCNE1, WNT1 and RASv12, in shp53 HMECs results in different and reproducible changes in mRNA and micro-RNA expression, copy number alterations (CNA) and DNA methylation profiles. Noticeably, HMECs transformed by RAS bore very specific profiles of CNAs and DNA methylation, clearly distinct from those shown by CCNE1 and WNT1 transformed HMECs. Genes impacted by CNAs and CpG methylation in the RAS and the CCNE1/WNT1 clusters showed clear differences, illustrating the activation of distinct pathways. Our data show that early activation of distinct oncogenic pathways leads to active adaptive events resulting in specific sets of CNAs and DNA methylation changes. We, thus, propose that activation of different oncogenes could have a role in reshaping the genetic landscape of breast cancer subtypes.
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http://dx.doi.org/10.1002/ijc.32413DOI Listing
September 2019

Coprs inactivation leads to a derepression of transposons in spermatocytes.

FEBS Open Bio 2019 01 19;9(1):159-168. Epub 2018 Dec 19.

Institut de Recherche en Cancérologie de Montpellier U1194, Inserm, ICM, CNRS, Montpellier University, Montpellier Cedex 5, France.

Repression of retrotransposons is essential for genome integrity during germ cell development and is tightly controlled through epigenetic mechanisms. In primordial germ cells, protein arginine -methyltransferase (Prmt5) is involved in retrotransposon repression by methylating Piwi proteins, which is part of the piRNA pathway. Here, we show that in mice, genetic inactivation of (which is highly expressed in testis and encodes a histone-binding protein required for the targeting of Prmt5 activity) affects the maturation of spermatogonia to spermatids. Mass spectrometry analysis revealed the presence of Miwi in testis protein lysates immunoprecipitated with an anti-Coprs antibody. The observed deregulation of Miwi and pachytene pre-piRNAs levels and the derepression of repetitive sequences observed in -/- mice suggest that Coprs is implicated in genome surveillance mechanisms.
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http://dx.doi.org/10.1002/2211-5463.12562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325579PMC
January 2019

Cell-cycle regulation of non-enzymatic functions of the Drosophila methyltransferase PR-Set7.

Nucleic Acids Res 2018 04;46(6):2834-2849

Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Institut Régional du Cancer (ICM), Montpellier F-34298, France.

Tight cell-cycle regulation of the histone H4-K20 methyltransferase PR-Set7 is essential for the maintenance of genome integrity. In mammals, this mainly involves the interaction of PR-Set7 with the replication factor PCNA, which triggers the degradation of the enzyme by the CRL4CDT2 E3 ubiquitin ligase. PR-Set7 is also targeted by the SCFβ-TRCP ligase, but the role of this additional regulatory pathway remains unclear. Here, we show that Drosophila PR-Set7 undergoes a cell-cycle proteolytic regulation, independently of its interaction with PCNA. Instead, Slimb, the ortholog of β-TRCP, is specifically required for the degradation of the nuclear pool of PR-Set7 prior to S phase. Consequently, inactivation of Slimb leads to nuclear accumulation of PR-Set7, which triggers aberrant chromatin compaction and G1/S arrest. Strikingly, these phenotypes result from non-enzymatic PR-Set7 functions that prevent proper histone H4 acetylation independently of H4K20 methylation. Altogether, these results identify the Slimb-mediated PR-Set7 proteolysis as a new critical regulatory mechanism required for proper interphase chromatin organization at G1/S transition.
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http://dx.doi.org/10.1093/nar/gky034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888314PMC
April 2018

Checkpoint kinase 1 inhibition sensitises transformed cells to dihydroorotate dehydrogenase inhibition.

Oncotarget 2017 Nov 12;8(56):95206-95222. Epub 2017 Jul 12.

Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.

Reduction in nucleotide pools through the inhibition of mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) has been demonstrated to effectively reduce cancer cell proliferation and tumour growth. The current study sought to investigate whether this antiproliferative effect could be enhanced by combining Chk1 kinase inhibition. The pharmacological activity of DHODH inhibitor teriflunomide was more selective towards transformed mouse embryonic fibroblasts than their primary or immortalised counterparts, and this effect was amplified when cells were subsequently exposed to PF477736 Chk1 inhibitor. Flow cytometry analyses revealed substantial accumulations of cells in S and G2/M phases, followed by increased cytotoxicity which was characterised by caspase 3-dependent induction of cell death. Associating PF477736 with teriflunomide also significantly sensitised SUM159 and HCC1937 human triple negative breast cancer cell lines to dihydroorotate dehydrogenase inhibition. The main characteristic of this effect was the sustained accumulation of teriflunomide-induced DNA damage as cells displayed increased phospho serine 139 H2AX (γH2AX) levels and concentration-dependent phosphorylation of Chk1 on serine 345 upon exposure to the combination as compared with either inhibitor alone. Importantly a similar significant increase in cell death was observed upon dual siRNA mediated depletion of Chk1 and DHODH in both murine and human cancer cell models. Altogether these results suggest that combining DHODH and Chk1 inhibitions may be a strategy worth considering as a potential alternative to conventional chemotherapies.
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http://dx.doi.org/10.18632/oncotarget.19199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707016PMC
November 2017

Histone H4K20 tri-methylation at late-firing origins ensures timely heterochromatin replication.

EMBO J 2017 09 4;36(18):2726-2741. Epub 2017 Aug 4.

Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Institut Régional du Cancer (ICM), Montpellier, France

Among other targets, the protein lysine methyltransferase PR-Set7 induces histone H4 lysine 20 monomethylation (H4K20me1), which is the substrate for further methylation by the Suv4-20h methyltransferase. Although these enzymes have been implicated in control of replication origins, the specific contribution of H4K20 methylation to DNA replication remains unclear. Here, we show that H4K20 mutation in mammalian cells, unlike in , partially impairs S-phase progression and protects from DNA re-replication induced by stabilization of PR-Set7. Using Epstein-Barr virus-derived episomes, we further demonstrate that conversion of H4K20me1 to higher H4K20me2/3 states by Suv4-20h is not sufficient to define an efficient origin , but rather serves as an enhancer for MCM2-7 helicase loading and replication activation at defined origins. Consistent with this, we find that Suv4-20h-mediated H4K20 tri-methylation (H4K20me3) is required to sustain the licensing and activity of a subset of ORCA/LRWD1-associated origins, which ensure proper replication timing of late-replicating heterochromatin domains. Altogether, these results reveal Suv4-20h-mediated H4K20 tri-methylation as a critical determinant in the selection of active replication initiation sites in heterochromatin regions of mammalian genomes.
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http://dx.doi.org/10.15252/embj.201796541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599798PMC
September 2017

E4F1 controls a transcriptional program essential for pyruvate dehydrogenase activity.

Proc Natl Acad Sci U S A 2016 09 12;113(39):10998-1003. Epub 2016 Sep 12.

Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM, U1194, Montpellier F-34298, France; Université Montpellier, Montpellier F-34090, France; Institut du Cancer Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France; Institut de Génétique Moléculaire de Montpellier, UMR5535, CNRS, Montpellier F-34293, France;

The mitochondrial pyruvate dehydrogenase (PDH) complex (PDC) acts as a central metabolic node that mediates pyruvate oxidation and fuels the tricarboxylic acid cycle to meet energy demand. Here, we reveal another level of regulation of the pyruvate oxidation pathway in mammals implicating the E4 transcription factor 1 (E4F1). E4F1 controls a set of four genes [dihydrolipoamide acetlytransferase (Dlat), dihydrolipoyl dehydrogenase (Dld), mitochondrial pyruvate carrier 1 (Mpc1), and solute carrier family 25 member 19 (Slc25a19)] involved in pyruvate oxidation and reported to be individually mutated in human metabolic syndromes. E4F1 dysfunction results in 80% decrease of PDH activity and alterations of pyruvate metabolism. Genetic inactivation of murine E4f1 in striated muscles results in viable animals that show low muscle PDH activity, severe endurance defects, and chronic lactic acidemia, recapitulating some clinical symptoms described in PDC-deficient patients. These phenotypes were attenuated by pharmacological stimulation of PDH or by a ketogenic diet, two treatments used for PDH deficiencies. Taken together, these data identify E4F1 as a master regulator of the PDC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5047171PMC
http://dx.doi.org/10.1073/pnas.1602754113DOI Listing
September 2016

E4F1-mediated control of pyruvate dehydrogenase activity is essential for skin homeostasis.

Proc Natl Acad Sci U S A 2016 09 12;113(39):11004-9. Epub 2016 Sep 12.

Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France;

The multifunctional protein E4 transcription factor 1 (E4F1) is an essential regulator of epidermal stem cell (ESC) maintenance. Here, we found that E4F1 transcriptionally regulates a metabolic program involved in pyruvate metabolism that is required to maintain skin homeostasis. E4F1 deficiency in basal keratinocytes resulted in deregulated expression of dihydrolipoamide acetyltransferase (Dlat), a gene encoding the E2 subunit of the mitochondrial pyruvate dehydrogenase (PDH) complex. Accordingly, E4f1 knock-out (KO) keratinocytes exhibited impaired PDH activity and a redirection of the glycolytic flux toward lactate production. The metabolic reprogramming of E4f1 KO keratinocytes associated with remodeling of their microenvironment and alterations of the basement membrane, led to ESC mislocalization and exhaustion of the ESC pool. ShRNA-mediated depletion of Dlat in primary keratinocytes recapitulated defects observed upon E4f1 inactivation, including increased lactate secretion, enhanced activity of extracellular matrix remodeling enzymes, and impaired clonogenic potential. Altogether, our data reveal a central role for Dlat in the metabolic program regulated by E4F1 in basal keratinocytes and illustrate the importance of PDH activity in skin homeostasis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5047149PMC
http://dx.doi.org/10.1073/pnas.1602751113DOI Listing
September 2016

Description of an optimized ChIP-seq analysis pipeline dedicated to genome wide identification of E4F1 binding sites in primary and transformed MEFs.

Genom Data 2015 Sep 14;5:368-70. Epub 2015 Jul 14.

Inserm U1194, Université Montpellier, Institut Régional du Cancer de Montpellier (ICM), 208 rue des Apothicaires, 34298 Montpellier, France.

This Data in Brief report describes the experimental and bioinformatic procedures that we used to analyze and interpret E4F1 ChIP-seq experiments published in Rodier et al. (2015) [10]. Raw and processed data are available at the GEO DataSet repository under the subseries # GSE57228. E4F1 is a ubiquitously expressed zinc-finger protein of the GLI-Kruppel family that was first identified in the late eighties as a cellular transcription factor targeted by the adenoviral oncoprotein E1A13S (Ad type V) and required for the transcription of adenoviral genes (Raychaudhuri et al., 1987) [8]. It is a multifunctional factor that also acts as an atypical E3 ubiquitin ligase for p53 (Le Cam et al., 2006) [2]. Using KO mouse models we then demonstrated that E4F1 is essential for early embryonic development (Le Cam et al., 2004), for proliferation of mouse embryonic cell (Rodier et al., 2015), for the maintenance of epidermal stem cells (Lacroix et al., 2010) [6], and strikingly, for the survival of cancer cells (Hatchi et al., 2007) [4]; (Rodier et al., 2015) [10]. The latter survival phenotype was p53-independent and suggested that E4F1 was controlling a transcriptional program driving essential functions in cancer cells. To identify this program, we performed E4F1 ChIP-seq analyses in primary Mouse Embryonic Fibroblasts (MEF) and in p53(-/-), H-Ras(V12)-transformed MEFs. The program directly controlled by E4F1 was obtained by intersecting the lists of E4F1 genomic targets with the lists of genes differentially expressed in E4F1 KO and E4F1 WT cells (Rodier et al., 2015). We describe hereby how we improved our ChIP-seq analyses workflow by applying prefilters on raw data and by using a combination of two publicly available programs, Cisgenome and QESEQ.
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http://dx.doi.org/10.1016/j.gdata.2015.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583703PMC
September 2015

The transcription factor E4F1 coordinates CHK1-dependent checkpoint and mitochondrial functions.

Cell Rep 2015 Apr 2;11(2):220-33. Epub 2015 Apr 2.

Equipe labellisée Ligue Contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR5535, Centre National de la Recherche Scientifique (CNRS), 34293 Montpellier, France; Institut de Recherche en Cancérologie de Montpellier (IRCM), 34298 Montpellier, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1194, 34298 Montpellier, France; Université de Montpellier, 34090 Montpellier, France; Institut régional du Cancer de Montpellier, 34298 Montpellier, France. Electronic address:

Recent data support the notion that a group of key transcriptional regulators involved in tumorigenesis, including MYC, p53, E2F1, and BMI1, share an intriguing capacity to simultaneously regulate metabolism and cell cycle. Here, we show that another factor, the multifunctional protein E4F1, directly controls genes involved in mitochondria functions and cell-cycle checkpoints, including Chek1, a major component of the DNA damage response. Coordination of these cellular functions by E4F1 appears essential for the survival of p53-deficient transformed cells. Acute inactivation of E4F1 in these cells results in CHK1-dependent checkpoint deficiency and multiple mitochondrial dysfunctions that lead to increased ROS production, energy stress, and inhibition of de novo pyrimidine synthesis. This deadly cocktail leads to the accumulation of uncompensated oxidative damage to proteins and extensive DNA damage, ending in cell death. This supports the rationale of therapeutic strategies simultaneously targeting mitochondria and CHK1 for selective killing of p53-deficient cancer cells.
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http://dx.doi.org/10.1016/j.celrep.2015.03.024DOI Listing
April 2015

The Wnt-target gene Dlk-1 is regulated by the Prmt5-associated factor Copr5 during adipogenic conversion.

Biol Open 2015 Feb 13;4(3):312-6. Epub 2015 Feb 13.

Equipe labellisée Ligue Contre le Cancer, Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, 34293 Montpellier, France Université Montpellier I and II, 34000 Montpellier, France Institut de Recherche en Cancérologie de Montpellier, Inserm, U1194, 34298 Montpellier, France

Protein arginine methyl transferase 5 (Prmt5) regulates various differentiation processes, including adipogenesis. Here, we investigated adipogenic conversion in cells and mice in which Copr5, a Prmt5- and histone-binding protein, was genetically invalidated. Compared to control littermates, the retroperitoneal white adipose tissue (WAT) of Copr5 KO mice was slightly but significantly reduced between 8 and 16 week/old and contained fewer and larger adipocytes. Moreover, the adipogenic conversion of Copr5 KO embryoid bodies (EB) and of primary embryo fibroblasts (Mefs) was markedly delayed. Differential transcriptomic analysis identified Copr5 as a negative regulator of the Dlk-1 gene, a Wnt target gene involved in the control of adipocyte progenitors cell fate. Dlk-1 expression was upregulated in Copr5 KO Mefs and the Vascular Stromal Fraction (VSF) of Copr5 KO WAT. Chromatin immunoprecipitation (ChIP) show that the ablation of Copr5 has impaired both the recruitment of Prmt5 and β-catenin at the Dlk-1 promoter. Overall, our data suggest that Copr5 is involved in the transcriptional control exerted by the Wnt pathway on early steps of adipogenesis.
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http://dx.doi.org/10.1242/bio.201411247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359737PMC
February 2015

Leukoencephalopathy with cysts and hyperglycinemia may result from NFU1 deficiency.

Mitochondrion 2014 Mar 22;15:59-64. Epub 2014 Jan 22.

Reference Center of Inherited Metabolic Diseases, University Paris Descartes, Hospital Necker Enfants Malades, APHP, Paris, France. Electronic address:

Lipoic acid metabolism defects are new metabolic disorders that cause neurological, cardiomuscular or pulmonary impairment. We report on a patient that presented with progressive neurological regression suggestive of an energetic disease, involving leukoencephalopathy with cysts. Elevated levels of glycine in plasma, urine and CSF associated with intermittent increases of lactate were consistent with a defect in lipoic acid metabolism. Support for the diagnosis was provided by pyruvate dehydrogenase deficiency and multiple mitochondrial respiratory chain deficiency in skin fibroblasts, as well as no lipoylated protein by western blot. Two mutations in the NFU1 gene confirmed the diagnosis. The p.Gly208Cys mutation has previously been reported suggesting a founder effect in Europe.
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http://dx.doi.org/10.1016/j.mito.2014.01.003DOI Listing
March 2014

Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase.

Orphanet J Rare Dis 2013 Dec 17;8:192. Epub 2013 Dec 17.

Reference Center of Inherited Metabolic Diseases, Imagine Institute, University Paris Descartes, Hospital Necker Enfants Malades, APHP, Paris, France.

Background: Synthesis and apoenzyme attachment of lipoic acid have emerged as a new complex metabolic pathway. Mutations in several genes involved in the lipoic acid de novo pathway have recently been described (i.e., LIAS, NFU1, BOLA3, IBA57), but no mutation was found so far in genes involved in the specific process of attachment of lipoic acid to apoenzymes pyruvate dehydrogenase (PDHc), α-ketoglutarate dehydrogenase (α-KGDHc) and branched chain α-keto acid dehydrogenase (BCKDHc) complexes.

Methods: Exome capture was performed in a boy who developed Leigh disease following a gastroenteritis and had combined PDH and α-KGDH deficiency with a unique amino acid profile that partly ressembled E3 subunit (dihydrolipoamide dehydrogenase / DLD) deficiency. Functional studies on patient fibroblasts were performed. Lipoic acid administration was tested on the LIPT1 ortholog lip3 deletion strain yeast and on patient fibroblasts.

Results: Exome sequencing identified two heterozygous mutations (c.875C > G and c.535A > G) in the LIPT1 gene that encodes a mitochondrial lipoyltransferase which is thought to catalyze the attachment of lipoic acid on PDHc, α-KGDHc, and BCKDHc. Anti-lipoic acid antibodies revealed absent expression of PDH E2, BCKDH E2 and α-KGDH E2 subunits. Accordingly, the production of 14CO2 by patient fibroblasts after incubation with 14Cglucose, 14Cbutyrate or 14C3OHbutyrate was very low compared to controls. cDNA transfection experiments on patient fibroblasts rescued PDH and α-KGDH activities and normalized the levels of pyruvate and 3OHbutyrate in cell supernatants. The yeast lip3 deletion strain showed improved growth on ethanol medium after lipoic acid supplementation and incubation of the patient fibroblasts with lipoic acid decreased lactate level in cell supernatants.

Conclusion: We report here a putative case of impaired free or H protein-derived lipoic acid attachment due to LIPT1 mutations as a cause of PDH and α-KGDH deficiencies. Our study calls for renewed efforts to understand the mechanisms of pathology of lipoic acid-related defects and their heterogeneous biochemical expression, in order to devise efficient diagnostic procedures and possible therapies.
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http://dx.doi.org/10.1186/1750-1172-8-192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905285PMC
December 2013

PRMT5-mediated histone H4 arginine-3 symmetrical dimethylation marks chromatin at G + C-rich regions of the mouse genome.

Nucleic Acids Res 2014 Jan 3;42(1):235-48. Epub 2013 Oct 3.

Institute of Molecular Genetics (IGMM), CNRS UMR 5535, University of Montpellier, 1919 route de Mende, 34293 Montpellier, Laboratoire Epigénétique et Destin Cellulaire, UMR7216, CNRS, Université Paris Diderot, 35 rue Hélène Brion, 75013 Paris, France and Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.

Symmetrical dimethylation on arginine-3 of histone H4 (H4R3me2s) has been reported to occur at several repressed genes, but its specific regulation and genomic distribution remained unclear. Here, we show that the type-II protein arginine methyltransferase PRMT5 controls H4R3me2s in mouse embryonic fibroblasts (MEFs). In these differentiated cells, we find that the genome-wide pattern of H4R3me2s is highly similar to that in embryonic stem cells. In both the cell types, H4R3me2s peaks are detected predominantly at G + C-rich regions. Promoters are consistently marked by H4R3me2s, independently of transcriptional activity. Remarkably, H4R3me2s is mono-allelic at imprinting control regions (ICRs), at which it marks the same parental allele as H3K9me3, H4K20me3 and DNA methylation. These repressive chromatin modifications are regulated independently, however, since PRMT5-depletion in MEFs resulted in loss of H4R3me2s, without affecting H3K9me3, H4K20me3 or DNA methylation. Conversely, depletion of ESET (KMT1E) or SUV420H1/H2 (KMT5B/C) affected H3K9me3 and H4K20me3, respectively, without altering H4R3me2s at ICRs. Combined, our data indicate that PRMT5-mediated H4R3me2s uniquely marks the mammalian genome, mostly at G + C-rich regions, and independently from transcriptional activity or chromatin repression. Furthermore, comparative bioinformatics analyses suggest a putative role of PRMT5-mediated H4R3me2s in chromatin configuration in the nucleus.
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http://dx.doi.org/10.1093/nar/gkt884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3874197PMC
January 2014

E4F1 dysfunction results in autophagic cell death in myeloid leukemic cells.

Autophagy 2011 Dec;7(12):1566-7

Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, IFR122, Montpellier, France.

The multifunctional E4F1 protein was originally identified as a cellular target of the E1A adenoviral oncoprotein. Although E4F1 is implicated in several key oncogenic pathways, its roles in tumorigenesis remain unclear. Using a genetically engineered mouse model of myeloid leukemia (histiocytic sarcomas, HS) based on the genetic inactivation of the tumor suppressor Ink4a/Arf locus, we have recently unraveled an unsuspected function of E4F1 in the survival of leukemic cells. In vivo, genetic ablation of E4F1 in established myeloid tumors results in tumor regression. E4F1 inactivation results in a cascade of alterations originating from dysfunctional mitochondria that induce increased reactive oxygen species (ROS) levels and ends in massive autophagic cell death in HS transformed, but not normal myeloid cells. E4F1 depletion also induces cell death in various human myeloid leukemic cell lines, including acute myeloid leukemic (AML) cell lines. Interestingly, the E4F1 protein is overexpressed in a large proportion of human AML samples. These data provide new insights into E4F1-associated survival functions implicated in tumorigenesis and could open the path for new therapeutic strategies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288034PMC
http://dx.doi.org/10.4161/auto.7.12.17991DOI Listing
December 2011

E4F1 deficiency results in oxidative stress-mediated cell death of leukemic cells.

J Exp Med 2011 Jul 27;208(7):1403-17. Epub 2011 Jun 27.

Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5535, Institut Fédératif de Recherche 122, Université de Montpellier, Montpellier 34293, France.

The multifunctional E4F1 protein was originally discovered as a target of the E1A viral oncoprotein. Growing evidence indicates that E4F1 is involved in key signaling pathways commonly deregulated during cell transformation. In this study, we investigate the influence of E4F1 on tumorigenesis. Wild-type mice injected with fetal liver cells from mice lacking CDKN2A, the gene encoding Ink4a/Arf, developed histiocytic sarcomas (HSs), a tumor originating from the monocytic/macrophagic lineage. Cre-mediated deletion of E4F1 resulted in the death of HS cells and tumor regression in vivo and extended the lifespan of recipient animals. In murine and human HS cell lines, E4F1 inactivation resulted in mitochondrial defects and increased production of reactive oxygen species (ROS) that triggered massive cell death. Notably, these defects of E4F1 depletion were observed in HS cells but not healthy primary macrophages. Short hairpin RNA-mediated depletion of E4F1 induced mitochondrial defects and ROS-mediated death in several human myeloid leukemia cell lines. E4F1 protein is overexpressed in a large subset of human acute myeloid leukemia samples. Together, these data reveal a role for E4F1 in the survival of myeloid leukemic cells and support the notion that targeting E4F1 activities might have therapeutic interest.
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http://dx.doi.org/10.1084/jem.20101995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135361PMC
July 2011

XIAP-associated factor 1 interacts with and attenuates the trans-activity of four and a Half LIM protein 2.

Mol Carcinog 2011 Mar 23;50(3):199-207. Epub 2010 Nov 23.

Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

XIAP-associated factor 1(XAF1) is a tumor suppressor with its functional mechanisms not fully understood. The zinc-finger cluster located at the N-terminus is the only domain structure. Four and a half LIM domain protein 2 (FHL2) also contains a tandem zinc finger structure, and its protein functions as an important adaptor and modifier in protein-protein interactions. Both of their structures are relatively simple, while the association between them is still unclear. In this study, we detected the interaction between XAF1 and FHL2 by using the yeast two-hybrid system. We identified FHL2 as a XAF1 binding protein. Furthermore, both XAF1 and FHL2 localized to the cytoplasm, mitochondria, and nucleus of gastric cancer cells. Over-expression of XAF1 excluded FHL2 from the nucleus and suppressed the trans-activity of FHL2 in stimulating the transcriptional activities of β-catenin and AP-1. In conclusion, our findings unraveled an antagonistic mechanism between a tumor suppressor and an oncoprotein in cancer cells.
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http://dx.doi.org/10.1002/mc.20705DOI Listing
March 2011

Transcription factor E4F1 is essential for epidermal stem cell maintenance and skin homeostasis.

Proc Natl Acad Sci U S A 2010 Dec 18;107(49):21076-81. Epub 2010 Nov 18.

Institut de Génétique Moléculaire de Montpellier, UMR5535, Centre National de la Recherche Scientifique, 34293 Montpellier, France.

A growing body of evidence suggests that the multifunctional protein E4F1 is involved in signaling pathways that play essential roles during normal development and tumorigenesis. We generated E4F1 conditional knockout mice to address E4F1 functions in vivo in newborn and adult skin. E4F1 inactivation in the entire skin or in the basal compartment of the epidermis induces skin homeostasis defects, as evidenced by transient hyperplasia in the interfollicular epithelium and alteration of keratinocyte differentiation, followed by loss of cellularity in the epidermis and severe skin ulcerations. E4F1 depletion alters clonogenic activity of epidermal stem cells (ESCs) ex vivo and ends in exhaustion of the ESC pool in vivo, indicating that the lesions observed in the E4F1 mutant skin result, at least in part, from cell-autonomous alterations in ESC maintenance. The clonogenic potential of E4F1 KO ESCs is rescued by Bmi1 overexpression or by Ink4a/Arf or p53 depletion. Skin phenotype of E4F1 KO mice is also delayed in animals with Ink4a/Arf and E4F1 compound gene deficiencies. Our data identify a regulatory axis essential for ESC-dependent skin homeostasis implicating E4F1 and the Bmi1-Arf-p53 pathway.
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http://dx.doi.org/10.1073/pnas.1010167107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3000279PMC
December 2010

The histone H4 Lys 20 methyltransferase PR-Set7 regulates replication origins in mammalian cells.

Nat Cell Biol 2010 Nov 17;12(11):1086-93. Epub 2010 Oct 17.

Institut de Génétique Moléculaire de Montpellier (IGMM), UMR 5535 CNRS, Montpellier, France.

The initiation of DNA synthesis is governed by the licensing of replication origins, which consists of assembling a pre-replication complex (pre-RC) on origins during late M- and G1-phases. In metazoans, functional replication origins do not show defined DNA consensus sequences, thus evoking the involvement of chromatin determinants in the selection of these origins. Here, we show that the onset of licensing in mammalian cells coincides with an increase in histone H4 Lys 20 monomethylation (H4K20me1) at replication origins by the methyltransferase PR-Set7 (also known as Set8 or KMT5A). Indeed, tethering PR-Set7 methylase activity to a specific genomic locus promotes the loading of pre-RC proteins on chromatin. In addition, we demonstrate that PR-Set7 undergoes a PCNA- and Cul4-Ddb1-driven degradation during S phase that contributes to the disappearance of H4K20me1 at origins and the inhibition of replication licensing. Strikingly, expression of a PR-Set7 mutant insensitive to this degradation causes the maintenance of H4K20me1 and repeated DNA replication at origins. These results elucidate a critical role for PR-Set7 and H4K20me1 in the chromatin events that regulate replication origins.
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http://dx.doi.org/10.1038/ncb2113DOI Listing
November 2010

Four and a half LIM protein 2 (FHL2) negatively regulates the transcription of E-cadherin through interaction with Snail1.

Eur J Cancer 2011 Jan;47(1):121-30

Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT), which plays a crucial role in cancer metastasis. We previously demonstrated that four and a half LIM protein 2 (FHL2) inhibited E-cadherin expression and promoted invasive potential and EMT in colon cancer. Here, we aim to further define the mechanism underlying the inhibition of E-cadherin by FHL2 in colon cancer. The expression profiles of FHL2 and Snail1 were first observed by Western blot, immunofluorescence and immunohistochemistry. We found that both the protein level and the cellular localisation of Snail1 were quite similar to FHL2 in colon cancer; reciprocal co-immunoprecipitation assay showed that FHL2 was able to bind Snail1 and its intact structure was required. The expression of FHL2 was positively correlated to Snail1 while negatively to E-cadherin and phospho-Snail1. FHL2 over-expression induced the accumulation of Snail1 in the nucleus. Moreover, dual luciferase assay revealed that FHL2 over-expression decreased while FHL2 siRNA increased the transcriptional activities of two E-cadherin promoter constructs which contained E-box sites (Snail1-binding elements). Mutation of E-boxes increased the transcriptional activities and FHL2 expression was involved in the function of mutation. These results suggested that FHL2 negatively regulated E-cadherin transcriptional activity through interaction with Snail1. Our study established a novel regulatory function of FHL2 and revealed a potential mechanism on promoting the process of EMT.
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http://dx.doi.org/10.1016/j.ejca.2010.07.045DOI Listing
January 2011

Abrogation of de novo lipogenesis by stearoyl-CoA desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer progression in mice.

Mol Cancer Ther 2010 Jun 8;9(6):1740-54. Epub 2010 Jun 8.

Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.

Increased de novo fatty acid (FA) synthesis is one hallmark of tumor cells, including prostate cancer. We present here our most recent results showing that lipid composition in human prostate cancer is characterized by an increased ratio of monounsaturated FA to saturated FA, compared with normal prostate, and evidence the overexpression of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) in human prostate cancer. As a new therapeutic strategy, we show that pharmacologic inhibition of SCD1 activity impairs lipid synthesis and results in decreased proliferation of both androgen-sensitive and androgen-resistant prostate cancer cells, abrogates the growth of prostate tumor xenografts in nude mice, and confers therapeutic benefit on animal survival. We show that these changes in lipid synthesis are translated into the inhibition of the AKT pathway and that the decrease in concentration of phosphatidylinositol-3,4,5-trisphosphate might at least partially mediate this effect. Inhibition of SCD1 also promotes the activation of AMP-activated kinase and glycogen synthase kinase 3alpha/beta, the latter on being consistent with a decrease in beta-catenin activity and mRNA levels of various beta-catenin growth-promoting transcriptional targets. Furthermore, we show that SCD1 activity is required for cell transformation by Ras oncogene. Together, our data support for the first time the concept of targeting the lipogenic enzyme SCD1 as a new promising therapeutic approach to block oncogenesis and prostate cancer progression.
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http://dx.doi.org/10.1158/1535-7163.MCT-09-1064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315476PMC
June 2010

Four-and-a-half LIM protein 2 promotes invasive potential and epithelial-mesenchymal transition in colon cancer.

Carcinogenesis 2010 Jul 11;31(7):1220-9. Epub 2010 May 11.

Guangdong Provincial key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Background And Aims: Cancer invasion and metastasis may associate with the phenotype transition called epithelial-mesenchymal transition (EMT). We aim to evaluate the impact of four-and-a-half LIM protein 2 (FHL2) on EMT and invasion of colon cancer.

Methods: The functional role of FHL2 in EMT was determined by overexpression or small interfering RNA-mediated depletion of FHL2. Mechanisms of FHL2 on expression or activity of E-cadherin and beta-catenin were assessed.

Results: FHL2 was highly expressed in primary and metastatic colon cancer but not in normal tissues. FHL2 was critical for cancer cell adhesion to extracellular matrix, migration and invasion. FHL2 expression was stimulated by transforming growth factor (TGF)-beta1. Moreover, FHL2 acted as a potent EMT inducer by stimulating vimentin and matrix metalloproteinase-9 expressions and causing a loss of E-cadherin, whereas those alterations of EMT markers were not affected by silencing of Smad molecules (typical TGF-beta signal mediators) in FHL2 stable transfectant cells. Therefore, FHL2 induced EMT in a TGF-beta-dependent and Smad-independent manner. FHL2 downregulated E-cadherin expression and inhibited the formation of membrane-associated E-cadherin-beta-catenin complex. FHL2 also stabilized nuclear beta-catenin, resulting in enforcement of beta-catenin transactivation activity.

Conclusion: FHL2 is a potent EMT inducer and might be an important mediator for invasion and/or metastasis of colon cancer.
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http://dx.doi.org/10.1093/carcin/bgq094DOI Listing
July 2010

Lessons from interconnected ubiquitylation and acetylation of p53: think metastable networks.

Biochem Soc Trans 2010 Feb;38(Pt 1):98-103

IGH, CNRS, UPR 1142, 141 rue de la Cardonille, 34396 Montpellier cedex 5, France.

The critical tumour suppressor p53 plays a major role in response to DNA damage and, more generally, to genotoxic stress. The regulation of its expression and functions is under very tight controls, and involves, in particular, an extremely complex set of post-translational modifications, thanks to a variety of 'modifiers', including ubiquitylation E3s and acetyltransferases, that fine-tune the stability and activity of the protein. Work of the last few years has revealed that, in addition to targeting p53, these modifiers also modify each other, forming an intricate network of regulatory molecules and events that must be taken into account to understand p53 regulation. We propose that this network allows a metastable equilibrium that confers both sensitivity and robustness on the p53 pathway, two properties that allow the pathway to respectively answer to a variety of stimuli and return to its initial stage when the stimuli disappear.
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http://dx.doi.org/10.1042/BST0380098DOI Listing
February 2010

The CDK4-pRB-E2F1 pathway controls insulin secretion.

Nat Cell Biol 2009 Aug 13;11(8):1017-23. Epub 2009 Jul 13.

INSERM, U834, Montpellier, F-34298, France.

CDK4-pRB-E2F1 cell-cycle regulators are robustly expressed in non-proliferating beta cells, suggesting that besides the control of beta-cell number the CDK4-pRB-E2F1 pathway has a role in beta-cell function. We show here that E2F1 directly regulates expression of Kir6.2, which is a key component of the K(ATP) channel involved in the regulation of glucose-induced insulin secretion. We demonstrate, through chromatin immunoprecipitation analysis from tissues, that Kir6.2 expression is regulated at the promoter level by the CDK4-pRB-E2F1 pathway. Consistently, inhibition of CDK4, or genetic inactivation of E2F1, results in decreased expression of Kir6.2, impaired insulin secretion and glucose intolerance in mice. Furthermore we show that rescue of Kir6.2 expression restores insulin secretion in E2f1(-/-) beta cells. Finally, we demonstrate that CDK4 is activated by glucose through the insulin pathway, ultimately resulting in E2F1 activation and, consequently, increased expression of Kir6.2. In summary we provide evidence that the CDK4-pRB-E2F1 regulatory pathway is involved in glucose homeostasis, defining a new link between cell proliferation and metabolism.
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http://dx.doi.org/10.1038/ncb1915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824657PMC
August 2009

PR-SET7 and SUV4-20H regulate H4 lysine-20 methylation at imprinting control regions in the mouse.

EMBO Rep 2008 Oct 22;9(10):998-1005. Epub 2008 Aug 22.

Institute of Molecular Genetics, CNRS and University of Montpellier, 1919 Route de Mende, 34293 Montpellier, France.

Imprinted genes are important in development and their allelic expression is mediated by imprinting control regions (ICRs). On their DNA-methylated allele, ICRs are marked by trimethylation at H3 Lys 9 (H3K9me3) and H4 Lys 20 (H4K20me3), similar to pericentric heterochromatin. Here, we investigate which histone methyltransferases control this methylation of histone at ICRs. We found that inactivation of SUV4-20H leads to the loss of H4K20me3 and increased levels of its substrate, H4K20me1. H4K20me1 is controlled by PR-SET7 and is detected on both parental alleles. The disruption of SUV4-20H or PR-SET7 does not affect methylation of DNA at ICRs but influences precipitation of H3K9me3, which is suggestive of a trans-histone change. Unlike at pericentric heterochromatin, however, H3K9me3 at ICRs does not depend on SUV39H. Our data show not only new similarities but also differences between ICRs and heterochromatin, both of which show constitutive maintenance of methylation of DNA in somatic cells.
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http://dx.doi.org/10.1038/embor.2008.147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2525564PMC
October 2008

The histone-binding protein COPR5 is required for nuclear functions of the protein arginine methyltransferase PRMT5.

EMBO Rep 2008 May 11;9(5):452-8. Epub 2008 Apr 11.

Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, Montpellier 34293, France.

Protein arginine methyltransferase 5 (PRMT5) targets nuclear and cytoplasmic proteins. Here, we identified a nuclear protein, called cooperator of PRMT5 (COPR5), involved in the nuclear functions of PRMT5. COPR5 tightly binds to PRMT5, both in vitro and in living cells, but not to other members of the PRMT family. PRMT5 bound to COPR5 methylates histone H4 (R3) preferentially when compared with histone H3 (R8), suggesting that COPR5 modulates the substrate specificity of nuclear PRMT5-containing complexes, at least towards histones. Markedly, recombinant COPR5 binds to the amino terminus of histone H4 and is required to recruit PRMT5 to reconstituted nucleosomes in vitro. Consistently, COPR5 depletion in cells strongly reduces PRMT5 recruitment on chromatin at the PRMT5 target gene cyclin E1 (CCNE1) in vivo. Moreover, both COPR5 depletion and overexpression affect CCNE1 promoter expression. We propose that COPR5 is an important chromatin adaptor for PRMT5 to function on a subset of its target genes.
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http://dx.doi.org/10.1038/embor.2008.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373370PMC
May 2008

PR-Set7-dependent lysine methylation ensures genome replication and stability through S phase.

J Cell Biol 2007 Dec 24;179(7):1413-26. Epub 2007 Dec 24.

University of Montpellier II, Institut de Génétique Moléculaire de Montpellier, 34293 Montpellier, Cedex 5, France.

PR-Set7/SET8 is a histone H4-lysine 20 methyltransferase required for normal cell proliferation. However, the exact functions of this enzyme remain to be determined. In this study, we show that human PR-Set7 functions during S phase to regulate cellular proliferation. PR-Set7 associates with replication foci and maintains the bulk of H4-K20 mono- and trimethylation. Consistent with a function in chromosome dynamics during S phase, inhibition of PR-Set7 methyltransferase activity by small hairpin RNA causes a replicative stress characterized by alterations in replication fork velocity and origin firing. This stress is accompanied by massive induction of DNA strand breaks followed by a robust DNA damage response. The DNA damage response includes the activation of ataxia telangiectasia mutated and ataxia telangiectasia related kinase-mediated pathways, which, in turn, leads to p53-mediated growth arrest to avoid aberrant chromosome behavior after improper DNA replication. Collectively, these data indicate that PR-Set7-dependent lysine methylation during S phase is an essential posttranslational mechanism that ensures genome replication and stability.
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http://dx.doi.org/10.1083/jcb.200706179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373513PMC
December 2007

E4F1 is an atypical ubiquitin ligase that modulates p53 effector functions independently of degradation.

Cell 2006 Nov;127(4):775-88

Institut de Génétique Moléculaire CNRS-UMII UMR5535, IFR122, Montpellier 34293, France.

p53 is regulated by multiple posttranslational modifications, including Hdm2-mediated ubiquitylation that drives its proteasomal degradation. Here, we identify the p53-associated factor E4F1, a ubiquitously expressed zinc-finger protein first identified as a cellular target of the viral oncoprotein E1A, as an atypical ubiquitin E3 ligase for p53 that modulates its effector functions without promoting proteolysis. E4F1 stimulates oligo-ubiquitylation in the hinge region of p53 on lysine residues distinct from those targeted by Hdm2 and previously described to be acetylated by the acetyltransferase PCAF. E4F1 and PCAF mediate mutually exclusive posttranslational modifications of p53. E4F1-dependent Ub-p53 conjugates are associated with chromatin, and their stimulation coincides with the induction of a p53-dependent transcriptional program specifically involved in cell cycle arrest, and not apoptosis. Collectively, our data reveal that E4F1 is a key posttranslational regulator of p53, which modulates its effector functions involved in alternative cell fates: growth arrest or apoptosis.
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http://dx.doi.org/10.1016/j.cell.2006.09.031DOI Listing
November 2006
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