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Dans le but de reconnaitre et répondre de manière efficace à une très grande variétés d agents pa... more Dans le but de reconnaitre et répondre de manière efficace à une très grande variétés d agents pathogènes, les cellules B ont développé au cours des mécanismes de diversifications des immunoglobulines contrôlés par des processus génétiques complexes comme la recombinaison V(D)J, l hypermutation somatiques (SHM), et le changement de classe par recombinaison (CSR). L ensemble de ces processus est contrôlé par différentes voies de réparations de l ADN. L anémie de Fanconi est une maladie génétique rare caractérisée par une défaillance progressive de la moelle osseuse, des anomalies de développement et un risque accru de développer des leucémies et des cancers oesopharyngés. La voie FANC est impliquée dans la réparation des pontages de l ADN et dans le maintien de la fourche de réplication en cas de stress génotoxique. Il est également bien décrit que la voie FANC joue un rôle important dans la coordination des voies de réponses aux dommages à l ADN. Dans ce travail de thèse, nous nous ...
Scientific Reports, 2016
B-lymphocytes in the bone marrow (BM) must generate a functional B-cell receptor and overcome the... more B-lymphocytes in the bone marrow (BM) must generate a functional B-cell receptor and overcome the negative selection induced by reactivity with autoantigens. Two rounds of DNA recombination are required for the production of functional immunoglobulin heavy (Ig-HCs) and light (LCs) chains necessary for the continuation of B-lymphocyte development in the BM. Both rounds depend on the joint action of recombination activating gene-1 (RAG-1) and RAG-2 endonucleases with the DNA nonhomologous end-joining pathway. Loss of the FANC gene leads to the chromosome breakage and cancer predisposition syndrome Fanconi anemia. Because the FANC proteins are involved in certain aspects of the recombination process, we sought to determine the impact of the FANC pathway on the Ig diversification process using Fanca −/− mice. In this work we demonstrated that Fanca −/− animals have a mild B-cell differentiation defect characterized by a specific alteration of the IgM − to IgM + transition of the B220 low B-cell population. Pre-B cells from Fanca −/− mice show evidence of impaired kLC rearrangement at the level of the Vk-Jk junction. Furthermore, Fanca −/− mice showed a skewed Vκ gene usage during formation of the LCs Vk-Jk junctions. Therefore, the Fanca protein appears as a yet unidentified factor involved in the primary diversification of Ig. To cope with the enormous variety of pathogens and to recognize non-self molecules, B-cells have evolved controlled genetic processes at their immunoglobulin (Ig) loci known as Ig diversification. Primary diversification occurs during early B-cell development in the bone marrow (BM) via the assembly of a complete IgM antigen receptor exposed on the B-cell surface (BCR) by a site-specific recombination process called V(D)J recombination. Mature B-cells that express a functional IgM migrate from the BM to the periphery, where antigen-dependent secondary diversification occurs following two activation-induced cytidine deaminase-dependent processes known as somatic hypermutation and class switch recombination (CSR) 1. To produce the Ig heavy chain (HC), V(D)J recombination starts in the BM at the pro-B cell stage by the D-to-J H rearrangement followed by the V H-to-DJ H rearrangement. Productive HC rearrangement leads to IgM-HC expression. After the assembly of the IgM-HC with a surrogate light chain (LC) and CD79a and b proteins, the IgM-HC is exposed on the cell surface as the precursor-B cell receptor (pre-BCR). Signals from the pre-BCR orchestrate the proliferation and subsequent developmental transition to the small pre-B-cell stage, where Igκ or Igλ LC VJ recombination is initiated 2,3. Successful pairing of a productive LC with an IgM-HC results in the expression of a BCR at the cell surface and progression to immature B cells, which are checked for autoreactivity before leaving the BM 4. V(D)J recombination depends on the action of the lymphoid-specific RAG-1 and RAG-2 endonucleases that initiate DNA cleavage at defined recombination signal sequences (RSS) that flank the V, D, and J gene segments. The RAG complex mediates the formation of two hairpinned extremities, called coding ends (CEs), cutting-off a DNA segment creating an one-ended blunted DSB at each extremity
Journal of Experimental Medicine, 2014
Fanca contributes to both somatic hypermutation and class switch recombination events in splenic ... more Fanca contributes to both somatic hypermutation and class switch recombination events in splenic B cells.
Dans le but de reconnaitre et répondre de manière efficace à une très grande variétés d agents pa... more Dans le but de reconnaitre et répondre de manière efficace à une très grande variétés d agents pathogènes, les cellules B ont développé au cours des mécanismes de diversifications des immunoglobulines contrôlés par des processus génétiques complexes comme la recombinaison V(D)J, l hypermutation somatiques (SHM), et le changement de classe par recombinaison (CSR). L ensemble de ces processus est contrôlé par différentes voies de réparations de l ADN. L anémie de Fanconi est une maladie génétique rare caractérisée par une défaillance progressive de la moelle osseuse, des anomalies de développement et un risque accru de développer des leucémies et des cancers oesopharyngés. La voie FANC est impliquée dans la réparation des pontages de l ADN et dans le maintien de la fourche de réplication en cas de stress génotoxique. Il est également bien décrit que la voie FANC joue un rôle important dans la coordination des voies de réponses aux dommages à l ADN. Dans ce travail de thèse, nous nous ...
Scientific Reports, 2016
B-lymphocytes in the bone marrow (BM) must generate a functional B-cell receptor and overcome the... more B-lymphocytes in the bone marrow (BM) must generate a functional B-cell receptor and overcome the negative selection induced by reactivity with autoantigens. Two rounds of DNA recombination are required for the production of functional immunoglobulin heavy (Ig-HCs) and light (LCs) chains necessary for the continuation of B-lymphocyte development in the BM. Both rounds depend on the joint action of recombination activating gene-1 (RAG-1) and RAG-2 endonucleases with the DNA nonhomologous end-joining pathway. Loss of the FANC gene leads to the chromosome breakage and cancer predisposition syndrome Fanconi anemia. Because the FANC proteins are involved in certain aspects of the recombination process, we sought to determine the impact of the FANC pathway on the Ig diversification process using Fanca −/− mice. In this work we demonstrated that Fanca −/− animals have a mild B-cell differentiation defect characterized by a specific alteration of the IgM − to IgM + transition of the B220 low B-cell population. Pre-B cells from Fanca −/− mice show evidence of impaired kLC rearrangement at the level of the Vk-Jk junction. Furthermore, Fanca −/− mice showed a skewed Vκ gene usage during formation of the LCs Vk-Jk junctions. Therefore, the Fanca protein appears as a yet unidentified factor involved in the primary diversification of Ig. To cope with the enormous variety of pathogens and to recognize non-self molecules, B-cells have evolved controlled genetic processes at their immunoglobulin (Ig) loci known as Ig diversification. Primary diversification occurs during early B-cell development in the bone marrow (BM) via the assembly of a complete IgM antigen receptor exposed on the B-cell surface (BCR) by a site-specific recombination process called V(D)J recombination. Mature B-cells that express a functional IgM migrate from the BM to the periphery, where antigen-dependent secondary diversification occurs following two activation-induced cytidine deaminase-dependent processes known as somatic hypermutation and class switch recombination (CSR) 1. To produce the Ig heavy chain (HC), V(D)J recombination starts in the BM at the pro-B cell stage by the D-to-J H rearrangement followed by the V H-to-DJ H rearrangement. Productive HC rearrangement leads to IgM-HC expression. After the assembly of the IgM-HC with a surrogate light chain (LC) and CD79a and b proteins, the IgM-HC is exposed on the cell surface as the precursor-B cell receptor (pre-BCR). Signals from the pre-BCR orchestrate the proliferation and subsequent developmental transition to the small pre-B-cell stage, where Igκ or Igλ LC VJ recombination is initiated 2,3. Successful pairing of a productive LC with an IgM-HC results in the expression of a BCR at the cell surface and progression to immature B cells, which are checked for autoreactivity before leaving the BM 4. V(D)J recombination depends on the action of the lymphoid-specific RAG-1 and RAG-2 endonucleases that initiate DNA cleavage at defined recombination signal sequences (RSS) that flank the V, D, and J gene segments. The RAG complex mediates the formation of two hairpinned extremities, called coding ends (CEs), cutting-off a DNA segment creating an one-ended blunted DSB at each extremity
Journal of Experimental Medicine, 2014
Fanca contributes to both somatic hypermutation and class switch recombination events in splenic ... more Fanca contributes to both somatic hypermutation and class switch recombination events in splenic B cells.