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6 results on '"Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer"'

1. Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia

Author

Marie Sebert, Stéphanie Gachet, Thierry Leblanc, Alix Rousseau, Olivier Bluteau, Rathana Kim, Raouf Ben Abdelali, Flore Sicre de Fontbrune, Loïc Maillard, Carèle Fedronie, Valentine Murigneux, Léa Bellenger, Naira Naouar, Samuel Quentin, Lucie Hernandez, Nadia Vasquez, Mélanie Da Costa, Pedro H. Prata, Lise Larcher, Marie de Tersant, Matthieu Duchmann, Anna Raimbault, Franck Trimoreau, Odile Fenneteau, Wendy Cuccuini, Nathalie Gachard, Nathalie Auger, Giulia Tueur, Maud Blanluet, Claude Gazin, Michèle Souyri, Francina Langa Vives, Aaron Mendez-Bermudez, Hélène Lapillonne, Etienne Lengline, Emmanuel Raffoux, Pierre Fenaux, Lionel Adès, Edouard Forcade, Charlotte Jubert, Carine Domenech, Marion Strullu, Bénédicte Bruno, Nimrod Buchbinder, Caroline Thomas, Arnaud Petit, Guy Leverger, Gérard Michel, Marina Cavazzana, Eliane Gluckman, Yves Bertrand, Nicolas Boissel, André Baruchel, Jean-Hugues Dalle, Emmanuelle Clappier, Eric Gilson, Ludovic Deriano, Sylvie Chevret, François Sigaux, Gérard Socié, Dominique Stoppa-Lyonnet, Hugues de Thé, Christophe Antoniewski, Dominique Bluteau, Régis Peffault de Latour, Jean Soulier, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP Hôpital universitaire Robert-Debré [Paris], Recherche clinique appliquée à l'hématologie (URP_3518), Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Limoges, Institut Gustave Roussy (IGR), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), CHU Nice [Cimiez], Hôpital Cimiez [Nice] (CHU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpitaux universitaires Est parisien [AP-HP], CHU Bordeaux [Bordeaux], Hospices Civils de Lyon (HCL), 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 Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Rouen, Normandie Université (NU), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), CIC NECKER BT (CIC 1416), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Collège de France (CdF (institution)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), This study received support from the European Research Council (ERC) Consolidator Grant to J.S. (CEVAL-311660), the FP7 Eurofancolen program (HEALTH-F5-2012-305421), the ANR program PACRI (Projet alliance parisienne des instituts de recherche en cancérologie), the CONECT-AML (Collaborative Network for Children and Teenagers with Acute Myeloid Leukemia) program supported by a grant from the Institut National du Cancer (INCa), Fondation ARC, Ligue nationale contre le cancer, and Laurette Fugain (INCa-ARC-LIGUE_11905) to J.S. and C.A., and the Association Française pour la Maladie de Fanconi (AFMF) grants 'Histoire naturelle de la maladie de Fanconi' to R.P.L. and J.S., 'Modélisation de la transformation leucémique dans la maladie de Fanconi' to D.B., and 'Cribles fonctionnels à haut débit de gènes modificateurs de la maladie de Fanconi' to C.G. M.S. was supported by the AVIESAN-INCa Program 'Formation à la Recherche Translationnelle,' and A.R. by a grant from the Fondation ARC. The work in E.G.’s lab is supported by Fondation ARC and ANR Telochrom. The work in L.D.’s lab is supported by INCa (PLBIO16-181) and ERC (310917)., ANR-11-PHUC-0002,PACRI,Alliance Parisienne des Instituts de Recherche en Cancérologie(2011), European Project: 311660,EC:FP7:ERC,ERC-2012-StG_20111109,CEVAL(2013), and European Project: 305421,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,EUROFANCOLEN(2013)

Subjects
MDM4, Fanconi anemia, precision medicine, [SDV]Life Sciences [q-bio], Genetics, leukemia, clonal hematopoiesis, Molecular Medicine, Cell Biology, TP53, mutational signature, genomic instability, BRCA2
Abstract

International audience; Fanconi anemia (FA) patients experience chromosome instability, yielding hematopoietic stem/progenitor cell (HSPC) exhaustion and predisposition to poor-prognosis myeloid leukemia. Based on a longitudinal cohort of 335 patients, we performed clinical, genomic, and functional studies in 62 patients with clonal evolution. We found a unique pattern of somatic structural variants and mutations that shares features of BRCA-related cancers, the FA-hallmark being unbalanced, microhomology-mediated translocations driving copy-number alterations. Half the patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4 trisomy downmodulating p53 signaling later followed by secondary acute myeloid lukemia genomic alterations. Functionally, MDM4 triplication conferred greater fitness to murine and human primary FA HSPCs, rescued inflammation-mediated bone marrow failure, and drove clonal dominance in FA mouse models, while targeting MDM4 impaired leukemia cells in vitro and in vivo. Our results identify a linear route toward secondary leukemogenesis whereby early MDM4-driven downregulation of basal p53 activation plays a pivotal role, opening monitoring and therapeutic prospects.

Published
2023
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2. V(D)J Recombination: Orchestrating Diversity Without Damage

Author

C. Lescale, L. Deriano, Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ralph A. Bradshaw, Gerald W. Hart, and Philip D. Stahl

Subjects
Genome instability, Genetics, Genomic instability, DNA repair, [SDV]Life Sciences [q-bio], V(D)J recombination, Biology, DNA damage response, Antigen receptor diversification, Recombination activating genes (RAGs) and V(D)J recombination, Immune system, Double-strand break, Leukemia and lymphoma, Immunodeficiency, Neoplastic transformation, Epigenetics, Lymphocyte, Gene, Recombination, NHEJ, Cancer
Abstract

International audience; V(D)J recombination assembles immunoglobulin and T-cell receptor genes from the preexisting variable (V), diversity (D), and joining (J) gene segments by a cut and paste mechanism. While this receptor diversification strategy enables efficient immune responses against pathogens, it also poses a constant threat to the genome integrity. Tight regulation of this process at multiple levels is therefore critical to prevent genomic instability and neoplastic transformation. In this article, we discuss the temporal and spatial regulation of V(D)J recombination, in addition to the molecular mechanisms that regulate this process. Finally, we discuss the implication of V(D)J recombination in malignancies of the immune system. “RAGs are the end-point of the strategies developed through evolution to achieve the anticipatory “Promethean” recognition of all universal molecular forms”. – A.A. de Freitas, Tractus Immuno-Logicus.

Published
2023
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3. SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination

Author

Estelle Vincendeau, Wenming Wei, Xuefei Zhang, Cyril Planchais, Wei Yu, Hélène Lenden-Hasse, Thomas Cokelaer, Juliana Pipoli da Fonseca, Hugo Mouquet, David J. Adams, Frederick W. Alt, Stephen P. Jackson, Gabriel Balmus, Chloé Lescale, Ludovic Deriano, Vincendeau, Estelle [0000-0002-0231-1609], Zhang, Xuefei [0000-0002-1873-6679], Yu, Wei [0000-0002-1777-5254], Cokelaer, Thomas [0000-0001-6286-1138], Adams, David J [0000-0001-9490-0306], Jackson, Stephen P [0000-0001-9317-7937], Balmus, Gabriel [0000-0003-2872-4468], Lescale, Chloé [0000-0003-0622-1149], Deriano, Ludovic [0000-0002-9673-9525], Apollo - University of Cambridge Repository, Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Howard Hughes Medical Institute (HHMI), Peking University [Beijing], Immunologie humorale - Humoral Immunology, Biomics (plateforme technologique), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, The Wellcome Trust Sanger Institute [Cambridge], University of Cambridge [UK] (CAM), The Deriano laboratory is funded by Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (Inserm), Wordwide Cancer Research (grant # 19-0333), Ligue Nationale Contre le Cancer (Equipe labellisée 2019), and Institut National du Cancer (INCa, grant # PLBIO19-122). E.V. is supported by the French Ministry of Higher Education, Research, and Innovation (Doctoral School Bio Sorbonne Paris Cité) and by the Fondation pour la Recherche Médicale. W.W. is part of the Pasteur–Paris University International Ph.D. program and received funding from the CNBG company, China. The Balmus laboratory at the UK DRI is funded by the Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. Research in the Jackson laboratory is funded by Cancer Research UK (CRUK) program grant DRCPGM\100005 and core grant C6946/A24843, Wellcome Investigator award 206388/Z/17/Z and core grant 203144, and ERC Synergy award 855741. S.P.J. receives a salary from the University of Cambridge. F.W.A is an investigator of the Howard Hughes Medical Institute. H.M. received core grants from the Institut Pasteur, the INSERM and the Milieu Intérieur Program (ANR-10-LABX-69-01)., We thank the Wellcome Trust Sanger Institute Mouse Genetics Project (Sanger MGP) and its funders for providing the mutant mouse line (Allele: Shld1em1(IMPC)Wtsi), and INFRAFRONTIER/EMMA. We thank the Institut Pasteur animal facility, specifically Quentin Mille, Jeromine Rohard Blanco, and Franck Bourgade for mouse weighing. We thank Jean-Pierre de Villartay for providing the CD21-Cre3a line and Klaus Rajewsky and MGC for permission to use the line. We thank Michela Di Virgilio for providing 53BP1 knockout animals and Junjie Chen for permission to use them. We thank members of the Deriano lab for their discussion and technical help. We thank Bernardo Reina-San-Martin for the discussion and advices. We thank Christopher Carnie for the discussion on the design of SHLD1 mutant sites., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), and Jackson, Stephen [0000-0001-9317-7937]

Subjects
DNA End-Joining Repair, MESH: V(D)J Recombination, [SDV]Life Sciences [q-bio], MESH: DNA Breaks, Double-Stranded, General Physics and Astronomy, 13/106, 45/23, 631/250/2152/2497, 631/250/2152/2498, General Biochemistry, Genetics and Molecular Biology, 13/1, 13/21, DNA Breaks, Double-Stranded, 631/337/1427/2122, Multidisciplinary, 45/71, 45, fungi, article, 45/77, General Chemistry, MESH: DNA End-Joining Repair, Immunoglobulin Class Switching, V(D)J Recombination, 49, DNA-Binding Proteins, 13/31, enzymes and coenzymes (carbohydrates), MESH: Immunoglobulin Class Switching, 631/337/149, MESH: DNA-Binding Proteins
Abstract

Funder: Ligue Nationale Contre le Cancer, SHLD1 is part of the Shieldin (SHLD) complex, which acts downstream of 53BP1 to counteract DNA double-strand break (DSB) end resection and promote DNA repair via non-homologous end-joining (NHEJ). While 53BP1 is essential for immunoglobulin heavy chain class switch recombination (CSR), long-range V(D)J recombination and repair of RAG-induced DSBs in XLF-deficient cells, the function of SHLD during these processes remains elusive. Here we report that SHLD1 is dispensable for lymphocyte development and RAG-mediated V(D)J recombination, even in the absence of XLF. By contrast, SHLD1 is essential for restricting resection at AID-induced DSB ends in both NHEJ-proficient and NHEJ-deficient B cells, providing an end-protection mechanism that permits productive CSR by NHEJ and alternative end-joining. Finally, we show that this SHLD1 function is required for orientation-specific joining of AID-initiated DSBs. Our data thus suggest that 53BP1 promotes V(D)J recombination and CSR through two distinct mechanisms: SHLD-independent synapsis of V(D)J segments and switch regions within chromatin, and SHLD-dependent protection of AID-DSB ends against resection.

Published
2022
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4. The Sec61 translocon is a therapeutic vulnerability in multiple myeloma

Author

Antoine Domenger, Caroline Choisy, Ludivine Baron, Véronique Mayau, Emeline Perthame, Ludovic Deriano, Bertrand Arnulf, Jean‐Christophe Bories, Gilles Dadaglio, Caroline Demangel, Immunobiologie de l'Infection - Immunobiology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Université Sorbonne Paris Cité (USPC), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the Cancéropôle Ile de France (CD and J-CB, Emergence 2019), the Fondation Française pour la Recherche contre le Myélome et les Gammapathies (CD, FFRMG), and the Sanofi iAwards program (CD, 2020). CD also acknowledges core support from Institut Pasteur and INSERM (U1221). LB was recipient of a Roux-Cantarini post-doctoral fellowship (Institut Pasteur). AD is a BioSPC-Université de Paris PhD student, recipient of a doctoral fellowship from the Ministère français de l’Enseignement Supérieur, de la Recherche et de l’Innovation., and Kop, Marie-Luce

Subjects
Sec61 translocon, Proteasome Endopeptidase Complex, [SDV.IMM] Life Sciences [q-bio]/Immunology, proteostatic stress, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Endoplasmic Reticulum Stress, [SDV] Life Sciences [q-bio], Mice, Protein Transport, Cell Line, Tumor, [SDV.IMM]Life Sciences [q-bio]/Immunology, Animals, Humans, Molecular Medicine, Multiple Myeloma, Proteasome Inhibitors, SEC Translocation Channels
Abstract

International audience; Multiple myeloma (MM) is an incurable malignancy characterized by the uncontrolled expansion of plasma cells in the bone marrow. While proteasome inhibitors like bortezomib efficiently halt MM progression, drug resistance inevitably develop, and novel therapeutic approaches are needed. Here, we used a recently discovered Sec61 inhibitor, mycolactone, to assess the interest of disrupting MM proteostasis via protein translocation blockade. In human MM cell lines, mycolactone caused rapid defects in secretion of immunoglobulins and expression of pro-survival interleukin (IL)-6 receptor and CD40, whose activation stimulates IL-6 production. Mycolactone also triggered pro-apoptotic endoplasmic reticulum stress responses synergizing with bortezomib for induction of MM cell death and overriding acquired resistance to the proteasome inhibitor. Notably, the mycolactone-bortezomib combination rapidly killed patient-derived MM cells ex vivo, but not normal mononuclear cells. In immunodeficient mice engrafted with MM cells, it demonstrated superior therapeutic efficacy over single drug treatments, without inducing toxic side effects. Collectively, these findings establish Sec61 blockers as novel anti-MM agents and reveal the interest of targeting both the translocon and the proteasome in proteostasis-addicted tumors.

Published
2022
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5. The (Lack of) DNA Double-Strand Break Repair Pathway Choice During V(D)J Recombination

Author

Libri, Alice, Marton, Timea, Deriano, Ludovic, Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and The Deriano laboratory is funded by Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (INSERM), Wordwide Cancer Research (grant # 19–0333), Ligue Nationale Contre le Cancer (Equipe labellis ée 2019) and Institut National du Cancer (INCa, grant # PLBIO19-122). AL received funding from Université de Paris, Sorbonne Paris Cité.

Subjects
DNA end resection, [SDV]Life Sciences [q-bio], fungi, DNA double-strand break repair pathway choice, Review, QH426-470, V(D)J recombination, non-homologous end-joining, enzymes and coenzymes (carbohydrates), homology-directed repair, DNA double-strand break, Genetics, Molecular Medicine, Genetics (clinical)
Abstract

International audience; DNA double-strand breaks (DSBs) are highly toxic lesions that can be mended via several DNA repair pathways. Multiple factors can influence the choice and the restrictiveness of repair towards a given pathway in order to warrant the maintenance of genome integrity. During V(D)J recombination, RAG-induced DSBs are (almost) exclusively repaired by the non-homologous end-joining (NHEJ) pathway for the benefit of antigen receptor gene diversity. Here, we review the various parameters that constrain repair of RAG-generated DSBs to NHEJ, including the peculiarity of DNA DSB ends generated by the RAG nuclease, the establishment and maintenance of a post-cleavage synaptic complex, and the protection of DNA ends against resection and (micro)homology-directed repair. In this physiological context, we highlight that certain DSBs have limited DNA repair pathway choice options.

Published
2022
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6. Fam72a enforces error-prone DNA repair during antibody diversification

Author

Michel Cogné, Brice Laffleur, Ophelie Martin, Bernardo Reina-San-Martin, Mélanie Rogier, Isabelle Robert, Jacques Moritz, Katia Capitani, Arthur Abello, Eric Pinaud, Florence Jouan, Ludovic Deriano, Anne-Sophie Thomas-Claudepierre, Vincent Heyer, Evi Soutoglou, Karin Tarte, Chloé Lescale, Morgane Thomas, Silvestro G. Conticello, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, Institut Pasteur [Paris], Physiopathologie du système immunitaire (Inserm U1223), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], University of Sussex, Università degli Studi di Siena = University of Siena (UNISI), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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 ), This study was supported by grants from the Fondation Recherche Médicale (Equipe FRM EQU201903007818 to B.R.-S.-M.), Institut National du Cancer (INCa_13852 to L.D. and B.R.-S.-M.), Fondation ARC (ARCPJA32020060002061 to B.R.-S.-M.), the Ligue Nationale contre le Cancer (Equipe labellisée to L.D.) and by the grant ANR-10-LABX-0030-INRT, a French state fund managed by the Agence Nationale de la Recherche under the program Investissements d’Avenir labelled ANR-10-IDEX-0002-02., ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-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 )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Université de Rennes (UR)-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 )

Subjects
Male, DNA damage, DNA repair, Somatic hypermutation, DNA Mismatch Repair, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Cytidine deamination, Animals, Uracil, 030304 developmental biology, 0303 health sciences, B-Lymphocytes, Multidisciplinary, Genome, Mutagenesis, Immunoglobulin Class Switching, 3. Good health, Cell biology, Immunoglobulin Switch Region, Up-Regulation, chemistry, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Uracil-DNA glycosylase, Mutation, DNA mismatch repair, Female, Somatic Hypermutation, Immunoglobulin, CRISPR-Cas Systems, DNA
Abstract

Efficient humoral responses rely on DNA damage, mutagenesis and error-prone DNA repair. Diversification of B cell receptors through somatic hypermutation and class-switch recombination are initiated by cytidine deamination in DNA mediated by activation-induced cytidine deaminase (AID)1 and by the subsequent excision of the resulting uracils by uracil DNA glycosylase (UNG) and by mismatch repair proteins1–3. Although uracils arising in DNA are accurately repaired1–4, how these pathways are co-opted to generate mutations and double-strand DNA breaks in the context of somatic hypermutation and class-switch recombination is unknown1–3. Here we performed a genome-wide CRISPR–Cas9 knockout screen for genes involved in class-switch recombination and identified FAM72A, a protein that interacts with the nuclear isoform of UNG (UNG2)5 and is overexpressed in several cancers5. We show that the FAM72A–UNG2 interaction controls the levels of UNG2 and that class-switch recombination is defective in Fam72a−/− B cells due to the upregulation of UNG2. Moreover, we show that somatic hypermutation is reduced in Fam72a−/− B cells and that its pattern is skewed upon upregulation of UNG2. Our results are consistent with a model in which FAM72A interacts with UNG2 to control its physiological level by triggering its degradation, regulating the level of uracil excision and thus the balance between error-prone and error-free DNA repair. Our findings have potential implications for tumorigenesis, as reduced levels of UNG2 mediated by overexpression of Fam72a would shift the balance towards mutagenic DNA repair, rendering cells more prone to acquire mutations. FAM72A interacts with UNG2 to regulate the balance between error-prone and error-free DNA repair.

Published
2021
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