Eléa Heberle - Academia.edu (original) (raw)
Papers by Eléa Heberle
Springer eBooks, 2015
Poly(ADP-ribosyl)ation is a post-translational modification of proteins in which ADP-ribose units... more Poly(ADP-ribosyl)ation is a post-translational modification of proteins in which ADP-ribose units are sequentially transferred from the substrate NAD+ to acceptor proteins on glutamate, aspartate or lysine residues. The enzymes that catalyse this process are commonly called poly(ADP-ribose) polymerases or PARPs. In human, 17 proteins have been gathered in the PARP superfamily, based on their sequence homology with the catalytic domain of its founding member, PARP-1. In the first part of this chapter, we will recapitulate the history of the discovery of the PARP superfamily. Several excellent reviews have already presented biological processes involving PARP proteins, describing their involvement in DNA repair, transcription, post-transcriptional regulation, stress immunity and inflammation or cancer (Feijs KL, Verheugd P, Luscher B (2013) Expanding functions of intracellular resident mono- ADP-ribosylation in cell physiology. FEBS J 280(15):3519–3529; Kleine H, Luscher B (2009) Learning how to read ADP-ribosylation. Cell 139(1):17–19; Gibson BA, Kraus WL (2012) New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol 13(7):411–424; Welsby I, Hutin D, Leo O (2012) Complex roles of members of the ADP-ribosyl transferase super family in immune defences: looking beyond PARP1. Biochem Pharmacol 84(1):11–20; Chambon P, Weill JD, Mandel P (1963) Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem Biophys Res Commun 11:39–43). During the past decades, researchers’ attention has mainly focused on the DNA-damage dependent PARPs and on tankyrases. In the second part of this chapter, we have chosen to present an exhaustive and thorough description of each PARP family member that has not been widely portrayed so far. For this reason, we will not describe the DNA-damage dependent PARPs, PARP-1, -2 and -3, reviewed in two other chapters of this book (Chap. 3). We will also not detail the tankyrases TNKS1 and TNKS2, objects of a distinct chapter too (Chap. 4). We will highlight the possible therapeutic avenues opened by the new biological roles that emerged for these highly promising PARP family members but still rather poorly characterized.
Essays in Biochemistry, 2019
Dynamic binding of transcription factors (TFs) to regulatory elements controls transcriptional st... more Dynamic binding of transcription factors (TFs) to regulatory elements controls transcriptional states throughout organism development. Epigenetics modifications, such as DNA methylation mostly within cytosine-guanine dinucleotides (CpGs), have the potential to modulate TF binding to DNA. Although DNA methylation has long been thought to repress TF binding, a more recent model proposes that TF binding can also inhibit DNA methylation. Here, we review the possible scenarios by which DNA methylation and TF binding affect each other. Further in vivo experiments will be required to generalize these models.
Frontiers in Molecular Neuroscience, Jul 29, 2022
The activation of the transient receptor potential (TRP) channels expressed by sensory neurons is... more The activation of the transient receptor potential (TRP) channels expressed by sensory neurons is essential to the transduction of thermal and mechanical sensory information. In the setting of chronic inflammatory conditions, the activation of the melastatin family member (TRPM), the TRP vanilloid (TRPV), and the TRP ankyrin (TRPA) is correlated with pain hypersensitivity reactions. Monoterpenes, among which pulegone and menthol, a major class of phytocompounds present in essential oils of medicinal plants, are known modulators of those TRP channels activity. In the present review, we correlate the monoterpene content of plants with their historical therapeutic properties. We then describe how monoterpenes exert their anti-inflammatory and antihyperalgesia e ects through modulation of TRP channels activity. Finally, we discuss the importance and the potential of characterizing new plant extracts and reassessing studied plant extracts for the development of ethnopharmacology-based innovative treatments for chronic pain. This review suggests that monoterpene solutions, based on composition from traditional healing herbs, o er an interesting avenue for the development of new phytotherapeutic treatments to alleviate chronic inflammatory pain conditions.
Frontiers in Pharmacology, Nov 30, 2021
Context: Menthol, the main monoterpene found in Mentha piperita L. (M. piperita) is known to modu... more Context: Menthol, the main monoterpene found in Mentha piperita L. (M. piperita) is known to modulate nociceptive threshold and is present in different curative preparations that reduce sensory hypersensitivities in pain conditions. While for pulegone, a menthol-like monoterpene, only a limited number of studies focus on its putative analgesic effects, pulegone is the most abundant monoterpene present in Calamintha nepeta (L.) Savi (C. nepeta), a plant of the Lamiaceae family used in traditional medicine to alleviate rheumatic disorders, which counts amongst chronic inflammatory diseases. Objectives: Here, we analyzed the monoterpenes composition of C. nepeta and M. piperita. We then compared the putative anti-hyperalgesic effects of the main monoterpenes found, menthol and pulegone, in acute inflammatory pain conditions. Methods: C. nepeta and M. piperita extracts were obtained through pressurized liquid extraction and analyzed by gas chromatography-mass spectrometry. The in vitro antiinflammatory activity of menthol or pulegone was evaluated by measuring the secretion of the tumour necrosis factor alpha (TNF α) from LPS-stimulated THP-1 cells. The in vivo antihyperalgesic effects of menthol and pulegone were tested on a rat inflammatory pain model. Results: Pulegone and menthol are the most abundant monoterpene found in C. nepeta (49.41%) and M. piperita (42.85%) extracts, respectively. In vitro, both pulegone and menthol act as strong anti-inflammatory molecules, with EC50 values of 1.2 ± 0.2 and 1.5 ± 0.1 mM, respectively, and exert cytotoxicity with EC50 values of 6.6 ± 0.3 and 3.5 ± 0.2 mM, respectively. In vivo, 100 mg/kg pulegone exerts a transient anti-hyperalgesic effect on both mechanical (pulegone: 274.
Methods in molecular biology, 2017
The purification of Poly(ADP-ribose) glycohydrolase (PARG) from over-expressing bacteria Escheric... more The purification of Poly(ADP-ribose) glycohydrolase (PARG) from over-expressing bacteria Escherichia coli is described here to a fast and reproducible one chromatographic step protocol. After cell lysis, GST-PARG-fusion proteins from the crude extract are affinity purified by a Glutathione 4B Sepharose chromatographic step. The PARG proteins are then freed from their GST-fusion by overnight enzymatic cleavage using the preScission protease. As described in the protocol, more than 500 µg of highly active human PARG can be obtained from 1.5 L of E. coli culture.
Bulletin du Cancer, 2015
Poly(ADP-ribosyl)ation is a post-translational modification catalyzed by poly(ADP-ribose) polymer... more Poly(ADP-ribosyl)ation is a post-translational modification catalyzed by poly(ADP-ribose) polymerases. PARP-1 is a molecular sensor of DNA breaks, playing a key role in the spatial and temporal organization of their repair, contributing to the maintenance of genome integrity and cell survival. The fact that PARP inhibition impairs efficacy of break repair has been exploited as anticancer strategies to potentiate the cytotoxicity of anticancer drugs and radiotherapy. Numerous clinical trials based on this innovative approach are in progress. PARP inhibition has also proved to be exquisitely efficient to kill tumour cells deficient in double strand break repair by homologous recombination, such as cells mutated for the breast cancer early onset genes BRCA1 or BRCA2, by synthetic lethality. Several phase III clinical trials are in progress for the treatment of breast and ovarian cancers with BRCA mutations and the PARP inhibitor olaparib has just been approved for advanced ovarian cancers with germline BRCA mutation. This review recapitulates the history from the discovery of poly(ADP-ribosyl)ation reaction to the promising therapeutic applications of its inhibition in innovating anticancer strategies. Benefits, hopes and obstacles are discussed.
La Poly(ADP-ribosyl)ation est une modification post-traductionnelle de protéines, impliquée dans ... more La Poly(ADP-ribosyl)ation est une modification post-traductionnelle de protéines, impliquée dans un grand nombre de processus biologiques, dont la réparation de l’ADN. Alors que la fonction et le mode d’action de la Poly(ADP-ribose) (PAR) Polymérase 1 (PARP1), activée en réponse aux dommages de l’ADN sont bien compris, on en sait beaucoup moins sur la fonction et la régulation de l’enzyme de dégradation du PAR, la Poly(ADP-ribose) glycohydrolase (PARG). Dans le contexte de ce projet de thèse, nous décrivons de nouvelles lignées U2OS stables, déficientes pour toutes les isoformes de PARG, permettant la complémentation inductible avec chacun des isoformes de PARG. Ces modèles nous ont permis d’évaluer les contributions relatives des isoformes à la réparation de dommages à l’ADN. Nous avons identifié un nouveau partenaire cellulaire de PARG : la protéine-kinase dépendante des dommages à l’ADN (DNA-PK). Nous explorons l’interaction fonctionnelle de ces deux protéines dans le contexte de...
A part of my initial PhD work aiming to elucidate the role and regulation of PARG isoforms produc... more A part of my initial PhD work aiming to elucidate the role and regulation of PARG isoforms production and post-translational modification in DNA repair.
La Poly(ADP-ribosyl)ation est une modification post-traductionnelle de proteines, impliquee dans ... more La Poly(ADP-ribosyl)ation est une modification post-traductionnelle de proteines, impliquee dans un grand nombre de processus biologiques, dont la reparation de l’ADN. Alors que la fonction et le mode d’action de la Poly(ADP-ribose) (PAR) Polymerase 1 (PARP1), activee en reponse aux dommages de l’ADN sont bien compris, on en sait beaucoup moins sur la fonction et la regulation de l’enzyme de degradation du PAR, la Poly(ADP-ribose) glycohydrolase (PARG). Dans le contexte de ce projet de these, nous decrivons de nouvelles lignees U2OS stables, deficientes pour toutes les isoformes de PARG, permettant la complementation inductible avec chacun des isoformes de PARG. Ces modeles nous ont permis d’evaluer les contributions relatives des isoformes a la reparation de dommages a l’ADN. Nous avons identifie un nouveau partenaire cellulaire de PARG : la proteine-kinase dependante des dommages a l’ADN (DNA-PK). Nous explorons l’interaction fonctionnelle de ces deux proteines dans le contexte de...
Springer eBooks, 2015
Poly(ADP-ribosyl)ation is a post-translational modification of proteins in which ADP-ribose units... more Poly(ADP-ribosyl)ation is a post-translational modification of proteins in which ADP-ribose units are sequentially transferred from the substrate NAD+ to acceptor proteins on glutamate, aspartate or lysine residues. The enzymes that catalyse this process are commonly called poly(ADP-ribose) polymerases or PARPs. In human, 17 proteins have been gathered in the PARP superfamily, based on their sequence homology with the catalytic domain of its founding member, PARP-1. In the first part of this chapter, we will recapitulate the history of the discovery of the PARP superfamily. Several excellent reviews have already presented biological processes involving PARP proteins, describing their involvement in DNA repair, transcription, post-transcriptional regulation, stress immunity and inflammation or cancer (Feijs KL, Verheugd P, Luscher B (2013) Expanding functions of intracellular resident mono- ADP-ribosylation in cell physiology. FEBS J 280(15):3519–3529; Kleine H, Luscher B (2009) Learning how to read ADP-ribosylation. Cell 139(1):17–19; Gibson BA, Kraus WL (2012) New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol 13(7):411–424; Welsby I, Hutin D, Leo O (2012) Complex roles of members of the ADP-ribosyl transferase super family in immune defences: looking beyond PARP1. Biochem Pharmacol 84(1):11–20; Chambon P, Weill JD, Mandel P (1963) Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem Biophys Res Commun 11:39–43). During the past decades, researchers’ attention has mainly focused on the DNA-damage dependent PARPs and on tankyrases. In the second part of this chapter, we have chosen to present an exhaustive and thorough description of each PARP family member that has not been widely portrayed so far. For this reason, we will not describe the DNA-damage dependent PARPs, PARP-1, -2 and -3, reviewed in two other chapters of this book (Chap. 3). We will also not detail the tankyrases TNKS1 and TNKS2, objects of a distinct chapter too (Chap. 4). We will highlight the possible therapeutic avenues opened by the new biological roles that emerged for these highly promising PARP family members but still rather poorly characterized.
Essays in Biochemistry, 2019
Dynamic binding of transcription factors (TFs) to regulatory elements controls transcriptional st... more Dynamic binding of transcription factors (TFs) to regulatory elements controls transcriptional states throughout organism development. Epigenetics modifications, such as DNA methylation mostly within cytosine-guanine dinucleotides (CpGs), have the potential to modulate TF binding to DNA. Although DNA methylation has long been thought to repress TF binding, a more recent model proposes that TF binding can also inhibit DNA methylation. Here, we review the possible scenarios by which DNA methylation and TF binding affect each other. Further in vivo experiments will be required to generalize these models.
Frontiers in Molecular Neuroscience, Jul 29, 2022
The activation of the transient receptor potential (TRP) channels expressed by sensory neurons is... more The activation of the transient receptor potential (TRP) channels expressed by sensory neurons is essential to the transduction of thermal and mechanical sensory information. In the setting of chronic inflammatory conditions, the activation of the melastatin family member (TRPM), the TRP vanilloid (TRPV), and the TRP ankyrin (TRPA) is correlated with pain hypersensitivity reactions. Monoterpenes, among which pulegone and menthol, a major class of phytocompounds present in essential oils of medicinal plants, are known modulators of those TRP channels activity. In the present review, we correlate the monoterpene content of plants with their historical therapeutic properties. We then describe how monoterpenes exert their anti-inflammatory and antihyperalgesia e ects through modulation of TRP channels activity. Finally, we discuss the importance and the potential of characterizing new plant extracts and reassessing studied plant extracts for the development of ethnopharmacology-based innovative treatments for chronic pain. This review suggests that monoterpene solutions, based on composition from traditional healing herbs, o er an interesting avenue for the development of new phytotherapeutic treatments to alleviate chronic inflammatory pain conditions.
Frontiers in Pharmacology, Nov 30, 2021
Context: Menthol, the main monoterpene found in Mentha piperita L. (M. piperita) is known to modu... more Context: Menthol, the main monoterpene found in Mentha piperita L. (M. piperita) is known to modulate nociceptive threshold and is present in different curative preparations that reduce sensory hypersensitivities in pain conditions. While for pulegone, a menthol-like monoterpene, only a limited number of studies focus on its putative analgesic effects, pulegone is the most abundant monoterpene present in Calamintha nepeta (L.) Savi (C. nepeta), a plant of the Lamiaceae family used in traditional medicine to alleviate rheumatic disorders, which counts amongst chronic inflammatory diseases. Objectives: Here, we analyzed the monoterpenes composition of C. nepeta and M. piperita. We then compared the putative anti-hyperalgesic effects of the main monoterpenes found, menthol and pulegone, in acute inflammatory pain conditions. Methods: C. nepeta and M. piperita extracts were obtained through pressurized liquid extraction and analyzed by gas chromatography-mass spectrometry. The in vitro antiinflammatory activity of menthol or pulegone was evaluated by measuring the secretion of the tumour necrosis factor alpha (TNF α) from LPS-stimulated THP-1 cells. The in vivo antihyperalgesic effects of menthol and pulegone were tested on a rat inflammatory pain model. Results: Pulegone and menthol are the most abundant monoterpene found in C. nepeta (49.41%) and M. piperita (42.85%) extracts, respectively. In vitro, both pulegone and menthol act as strong anti-inflammatory molecules, with EC50 values of 1.2 ± 0.2 and 1.5 ± 0.1 mM, respectively, and exert cytotoxicity with EC50 values of 6.6 ± 0.3 and 3.5 ± 0.2 mM, respectively. In vivo, 100 mg/kg pulegone exerts a transient anti-hyperalgesic effect on both mechanical (pulegone: 274.
Methods in molecular biology, 2017
The purification of Poly(ADP-ribose) glycohydrolase (PARG) from over-expressing bacteria Escheric... more The purification of Poly(ADP-ribose) glycohydrolase (PARG) from over-expressing bacteria Escherichia coli is described here to a fast and reproducible one chromatographic step protocol. After cell lysis, GST-PARG-fusion proteins from the crude extract are affinity purified by a Glutathione 4B Sepharose chromatographic step. The PARG proteins are then freed from their GST-fusion by overnight enzymatic cleavage using the preScission protease. As described in the protocol, more than 500 µg of highly active human PARG can be obtained from 1.5 L of E. coli culture.
Bulletin du Cancer, 2015
Poly(ADP-ribosyl)ation is a post-translational modification catalyzed by poly(ADP-ribose) polymer... more Poly(ADP-ribosyl)ation is a post-translational modification catalyzed by poly(ADP-ribose) polymerases. PARP-1 is a molecular sensor of DNA breaks, playing a key role in the spatial and temporal organization of their repair, contributing to the maintenance of genome integrity and cell survival. The fact that PARP inhibition impairs efficacy of break repair has been exploited as anticancer strategies to potentiate the cytotoxicity of anticancer drugs and radiotherapy. Numerous clinical trials based on this innovative approach are in progress. PARP inhibition has also proved to be exquisitely efficient to kill tumour cells deficient in double strand break repair by homologous recombination, such as cells mutated for the breast cancer early onset genes BRCA1 or BRCA2, by synthetic lethality. Several phase III clinical trials are in progress for the treatment of breast and ovarian cancers with BRCA mutations and the PARP inhibitor olaparib has just been approved for advanced ovarian cancers with germline BRCA mutation. This review recapitulates the history from the discovery of poly(ADP-ribosyl)ation reaction to the promising therapeutic applications of its inhibition in innovating anticancer strategies. Benefits, hopes and obstacles are discussed.
La Poly(ADP-ribosyl)ation est une modification post-traductionnelle de protéines, impliquée dans ... more La Poly(ADP-ribosyl)ation est une modification post-traductionnelle de protéines, impliquée dans un grand nombre de processus biologiques, dont la réparation de l’ADN. Alors que la fonction et le mode d’action de la Poly(ADP-ribose) (PAR) Polymérase 1 (PARP1), activée en réponse aux dommages de l’ADN sont bien compris, on en sait beaucoup moins sur la fonction et la régulation de l’enzyme de dégradation du PAR, la Poly(ADP-ribose) glycohydrolase (PARG). Dans le contexte de ce projet de thèse, nous décrivons de nouvelles lignées U2OS stables, déficientes pour toutes les isoformes de PARG, permettant la complémentation inductible avec chacun des isoformes de PARG. Ces modèles nous ont permis d’évaluer les contributions relatives des isoformes à la réparation de dommages à l’ADN. Nous avons identifié un nouveau partenaire cellulaire de PARG : la protéine-kinase dépendante des dommages à l’ADN (DNA-PK). Nous explorons l’interaction fonctionnelle de ces deux protéines dans le contexte de...
A part of my initial PhD work aiming to elucidate the role and regulation of PARG isoforms produc... more A part of my initial PhD work aiming to elucidate the role and regulation of PARG isoforms production and post-translational modification in DNA repair.
La Poly(ADP-ribosyl)ation est une modification post-traductionnelle de proteines, impliquee dans ... more La Poly(ADP-ribosyl)ation est une modification post-traductionnelle de proteines, impliquee dans un grand nombre de processus biologiques, dont la reparation de l’ADN. Alors que la fonction et le mode d’action de la Poly(ADP-ribose) (PAR) Polymerase 1 (PARP1), activee en reponse aux dommages de l’ADN sont bien compris, on en sait beaucoup moins sur la fonction et la regulation de l’enzyme de degradation du PAR, la Poly(ADP-ribose) glycohydrolase (PARG). Dans le contexte de ce projet de these, nous decrivons de nouvelles lignees U2OS stables, deficientes pour toutes les isoformes de PARG, permettant la complementation inductible avec chacun des isoformes de PARG. Ces modeles nous ont permis d’evaluer les contributions relatives des isoformes a la reparation de dommages a l’ADN. Nous avons identifie un nouveau partenaire cellulaire de PARG : la proteine-kinase dependante des dommages a l’ADN (DNA-PK). Nous explorons l’interaction fonctionnelle de ces deux proteines dans le contexte de...