6 results on '"Anthony Perrot"'
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2. CDK activity provides temporal and quantitative cues for organizing genome duplication.
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Anthony Perrot, Christopher Lee Millington, Blanca Gómez-Escoda, Diane Schausi-Tiffoche, and Pei-Yun Jenny Wu
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Genetics ,QH426-470 - Abstract
In eukaryotes, the spatial and temporal organization of genome duplication gives rise to distinctive profiles of replication origin usage along the chromosomes. While it has become increasingly clear that these programs are important for cellular physiology, the mechanisms by which they are determined and modulated remain elusive. Replication initiation requires the function of cyclin-dependent kinases (CDKs), which associate with various cyclin partners to drive cell proliferation. Surprisingly, although we possess detailed knowledge of the CDK regulators and targets that are crucial for origin activation, little is known about whether CDKs play a critical role in establishing the genome-wide pattern of origin selection. We have addressed this question in the fission yeast, taking advantage of a simplified cell cycle network in which cell proliferation is driven by a single cyclin-CDK module. This system allows us to precisely control CDK activity in vivo using chemical genetics. First, in contrast to previous reports, our results clearly show that distinct cyclin-CDK pairs are not essential for regulating specific subsets of origins and for establishing a normal replication program. Importantly, we then demonstrate that the timing at which CDK activity reaches the S phase threshold is critical for the organization of replication in distinct efficiency domains, while the level of CDK activity at the onset of S phase is a dose-dependent modulator of overall origin efficiencies. Our study therefore implicates these different aspects of CDK regulation as versatile mechanisms for shaping the architecture of DNA replication across the genome.
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- 2018
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3. MiR-31-3p do not predict anti-EGFR efficacy in first-line therapy of RAS wild-type metastatic right-sided colon cancer
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Emeric Boisteau, Alexandra Lespagnol, Marie De Tayrac, Sébastien Corre, Anthony Perrot, Nathalie Rioux-Leclercq, Séverine Martin-Lannerée, Pascal Artru, Philippe Chalabreysse, Pierre-Guillaume Poureau, Laurent Doucet, Dahna Coupez, Jaafar Bennouna, Céline Bossard, Romain Coriat, Frédéric Beuvon, Lucile Bauguion, François Leclair, Romain Chautard, Thierry Lecomte, Serge Guyetant, Romain Desgrippes, Denis Grasset, Hélène Lhostis, Karine Bouhier-Leporrier, Frédéric Bibeau, Julien Edeline, Marie-Dominique Galibert, Astrid Lièvre, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), IntegraGen, Hôpital privé Jean Mermoz [Lyon], Cypath : siège social [Villeurbanne], University Hospital Gasthuisberg, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Départemental Vendée (CHDV), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CH de Saint-Malo [Broussais], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire [Rennes], CRLCC Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncogenesis, Stress, Signaling (OSS), This research received no external funding. We thank the Rennes University Hospital and the Centre d'Etude des Maladies Digestives de Rennes (CEMDR) for their financial support. Anthony Perrot was financially supported by the Rennes University Hospital., Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University Hospital Gasthuisberg [Leuven], and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Hepatology ,[SDV]Life Sciences [q-bio] ,Gastroenterology ,colorectal cancer ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,miR-31-3p ,anti-EGFR mAb ,Bevacizumab ,ErbB Receptors ,MicroRNAs ,Antineoplastic Combined Chemotherapy Protocols ,Colonic Neoplasms ,biomarker ,metastasis ,Humans ,Colorectal Neoplasms ,Retrospective Studies - Abstract
International audience; BACKGROUND: Low miR-31-3p expression was identified as predictive of anti-EGFR efficacy in RAS-wt mCRC. Primary tumor side was also proposed as a predictive factor of anti-EGFR benefit. This retrospective multicentric study evaluated the predictive role of miR-31-3p in right-sided RAS-wt mCRC patients treated with first-line CT+anti-EGFR or CT+bevacizumab (Beva). METHODS: Seventy-two right-sided RAS-wt mCRC patients treated in first-line with CT+anti-EGFR (n=43) or Beva (n=29) were included. Overall survival (OS), progression-free survival (PFS) and response rate (RR) were analyzed and stratified according to tumor miR-31-3p expression level and targeted therapy (TT). RESULTS: BRAF V600E mutation was more frequent in high vs low miR-31-3p expressers (60.6% vs 15.4%, P < 0.001). PFS was significantly longer with CT+Beva than with CT+anti-EGFR (13 vs 7 months; P = 0.024). Among low miR-31-3p expressers, PFS, OS and RR were not significantly different between the two groups, while in high miR-31-3p expressers, only PFS was longer in the CT+Beva group (11 vs 6 months; P = 0.03). In patients treated with CT+anti-EGFR, low miR-31-3p expressers had a significantly longer OS (20 vs 13 months; P = 0.02) than high miR-31-3p expressers. ORR was not significantly different between the two groups of treatment, in both low and high miR-31-3p expressers. MiR-31-3p expression status was statistically correlated between primary tumors and corresponding metastases. CONCLUSION: In this study, miR-31-3p couldn’t identify a subgroup of patients with right-sided RAS-wt mCRC who might benefit from anti-EGFR and suggest that Beva is the TT of choice in first-line treatment of these patients.
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- 2021
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4. Impact of Chromosomal Context on Origin Selection and the Replication Program
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Lilian Lanteri, Anthony Perrot, Diane Schausi-Tiffoche, Pei-Yun Jenny Wu, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Marie Curie Career Integration Grant from the 7th Framework Programme of the European Commission [334200], Chair for Emergence, Science, and Society program of the Region Nouvelle Aquitaine, Ligue Contre le Cancer Grand-Ouest, and Fondation ARC
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DNA Replication ,replication program ,genome rearrangements ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Genetics ,Replication Origin ,Genome, Fungal ,chromosomal architecture ,fission yeast ,Genetics (clinical) ,Chromosomes ,DNA replication ,S Phase - Abstract
International audience; Eukaryotic DNA replication is regulated by conserved mechanisms that bring about a spatial and temporal organization in which distinct genomic domains are copied at characteristic times during S phase. Although this replication program has been closely linked with genome architecture, we still do not understand key aspects of how chromosomal context modulates the activity of replication origins. To address this question, we have exploited models that combine engineered genomic rearrangements with the unique replication programs of post-quiescence and pre-meiotic S phases. Our results demonstrate that large-scale inversions surprisingly do not affect cell proliferation and meiotic progression, despite inducing a restructuring of replication domains on each rearranged chromosome. Remarkably, these alterations in the organization of DNA replication are entirely due to changes in the positions of existing origins along the chromosome, as their efficiencies remain virtually unaffected genome wide. However, we identified striking alterations in origin firing proximal to the fusion points of each inversion, suggesting that the immediate chromosomal neighborhood of an origin is a crucial determinant of its activity. Interestingly, the impact of genome reorganization on replication initiation is highly comparable in the post-quiescent and pre-meiotic S phases, despite the differences in DNA metabolism in these two physiological states. Our findings therefore shed new light on how origin selection and the replication program are governed by chromosomal architecture.
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- 2022
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5. Identification of a novel CTNNA1 germline mutation predisposing to melanoma: Genotype and functional effects
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Thomas Roret, A. Forestier, Anne-Gaëlle Rio, Sébastien Corre, Agnès Burel, Laure Masson, Sarah Guégan, Ludivine Percevault, Lise Boussemart, Catherine Prost, Arnaud de la Fouchardière, Patrick R. Benusiglio, Sophie Fromentoux, Anthony Perrot, Siraj M. Ali, Alain Dupuy, Alexandra Lespagnol, Brigitte M Bressac-de Paillerets, David Gilot, Marie-Dominique Galibert, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Société Française de Dermatologie, Other Foundation, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1)
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Genetics ,Cancer Research ,business.industry ,Melanoma ,[SDV]Life Sciences [q-bio] ,Context (language use) ,medicine.disease ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Oncology ,030220 oncology & carcinogenesis ,Genotype ,Medicine ,Identification (biology) ,business ,ComputingMilieux_MISCELLANEOUS ,030215 immunology - Abstract
e21592 Background: While 10% of melanomas occur in a context suggesting hereditary predisposition, a clear molecular explanation has only been established for approximately 20% of families. In the course of clinical care, we identified a new CTNNA1 truncating germline mutation in a family affected by multiple early-onset melanomas. Methods: NGS and CGH-array were performed on the index case’s melanoma, followed by Sanger sequencing of the germline DNA of relatives. Immunochemistry (IHC) was employed to evaluate the level of αE-catenin (encoded by CTNNA1) in the family's samples. Stable CTNNA1 knockout human melanoma cell lines were generated to investigate the functional effects of CTNNA1 loss. Functional assays, including colony formation, 3-D tumor spheroid formation, wound healing, and transwell invasion were performed, as well as electron microscopy and RNAsequencing (RNAseq). CTNNA1 mutational status was determined in several databases and further sequencing of CTNNA1 in a DNA bank of families with multiple melanomas was done. Results: While the allele frequency in the index patient’s tumoral DNA was compatible with a germline mutation, the CTNNA1 F611fs*10 mutation was subsequently found cosegregating with individuals affected by melanoma in the family. CGH array on tumor DNA identified a segmental loss on chromosome 5, leading to a loss of heterozygosity of CTNNA1, resulting in a loss of αE-catenin observed by IHC. Clinically, the mean age of first melanoma diagnosis was 29,7 years (range: 18-56), 2 were metastatic, and the others were SSM (superficial spreading melanoma) in situ (n = 3) or Breslow index 0,56 mm (n = 1). Functional assays performed on CTNNA1 KO melanoma cell lines showed a loss of cell-to-cell adhesion phenotype, in accordance with the altered adherens junctions observed by electron microscopy, and the specific pathway enrichments observed by RNAseq. This specific phenotype could be rescued by transfection with a plasmid containing wild-type CTNNA1, as opposed to the CTNNA1 F611fs* plasmid. Germline CTNNA1 mutations are rare as none could be further identified in a DNA bank of 27 multiple melanoma families. In a database of 4743 melanomas somatically sequenced for CTNNA1, 131 of them had a CTNNA1 alteration (2,76%), with a median tumor mutational burden of 44 mut/MB of DNA (range from 0 to 451). Among them, 15 alterations were predicted to be inactivating, including 7 associated with a BRAF or NRAS activating mutation. Conclusions: Altogether, our results strongly support that CTNNA1 loss of function predisposes to melanoma formation characterized by a decreased cell adhesion. Since germline CTNNA1 alterations have already been implicated in lobular breast cancers and hereditary diffuse gastric cancers, CTNNA1 likely constitutes a tumor suppressor gene involved in familial melanoma, thus broadening the spectrum of syndromes associated with this gene.
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- 2021
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6. Toward Libraries of Biotinylated Chondroitin Sulfate Analogues: From Synthesis to In Vivo Studies
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Laurent Cattiaux, Hugues Lortat-Jacob, Guillaume Despras, Anthony Perrot, Alain Prochiantz, Jean-Maurice Mallet, Clémence Bernard, Université Pierre et Marie Curie - Paris 6 (UPMC), Collège de France - Chaire Processus morphogénétiques, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Chaire Processus morphogénétiques, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
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Anomer ,Stereochemistry ,Epoxide ,Chemistry Techniques, Synthetic ,01 natural sciences ,Catalysis ,Small Molecule Libraries ,03 medical and health sciences ,chemistry.chemical_compound ,Cell Line, Tumor ,Humans ,Biotinylation ,Chondroitin sulfate ,030304 developmental biology ,0303 health sciences ,010405 organic chemistry ,Chemistry ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,Organic Chemistry ,Chondroitin Sulfates ,General Chemistry ,HEXA ,0104 chemical sciences ,Click chemistry ,Sodium azide ,Click Chemistry ,Selectivity - Abstract
International audience; Chondroitin sulfate-E (CS-E) oligosaccharidic analogues (di to hexa) were prepared from lactose. In these compounds, the 2-acetamido group was replaced by a hydroxyl group. This modification speeded up the synthesis, and large oligosaccharides were constructed in a few steps from a lactose-originated block. The protecting groups used were as follows; Fmoc for hydroxyl groups to be glycosylated, allyl group for anomeric position protection, and trichoroacetimidate leaving groups were used to prepare up to octasaccharides. We took advantage of the presence of allyl group to develop a click biotinylation, through its transformation into a 3-azido-2-hydroxyl propyl group in two steps (epoxidation and sodium azide epoxide opening). The biotinylating agent was a water-soluble propargylated and biotinylated triethylene glycol (PEG). By using surface plasmon resonance (SPR), it was shown that the di-, tetra-, and hexasaccharides display a binding affinity and selectivity toward HSF/GSF and CXCL12 similar to that of CS-E. A parallel study confirmed their mimicry of natural compounds, based on the hexasaccharide interaction with Otx2, a homeodomain protein involved in brain maturation, thus validating our simplification approach to synthesize bioactive GAG.
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- 2013
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