RESUMEN
The DNA double-strand break (DSB) repair factor 53BP1 has long been implicated in V(D)J and class switch recombination (CSR) of mammalian lymphocyte receptors. However, the dissection of the underlying molecular activities is hampered by a paucity of studies [V(D)J] and plurality of phenotypes (CSR) associated with 53BP1 deficiency. Here, we revisit the currently accepted roles of 53BP1 in antibody diversification in view of the recent identification of its downstream effectors in DSB protection and latest advances in genome architecture. We propose that, in addition to end protection, 53BP1-mediated end-tethering stabilization is essential for CSR. Furthermore, we support a pre-DSB role during V(D)J recombination. Our perspective underscores the importance of evaluating repair of DSBs in relation to their dynamic architectural contexts.
Asunto(s)
Anticuerpos , Roturas del ADN de Doble Cadena , Reparación del ADN , Proteína 1 de Unión al Supresor Tumoral P53 , Animales , Humanos , Ratones , Anticuerpos/genética , Cambio de Clase de Inmunoglobulina/genética , Linfocitos , MamíferosRESUMEN
Forkhead box class O1 (FOXO1) acts as a tumor suppressor in solid tumors. The oncogenic phosphoinositide-3-kinase (PI3K) pathway suppresses FOXO1 transcriptional activity by enforcing its nuclear exclusion upon AKT-mediated phosphorylation. We show here abundant nuclear expression of FOXO1 in Burkitt lymphoma (BL), a germinal center (GC) B-cell-derived lymphoma whose pathogenesis is linked to PI3K activation. Recurrent FOXO1 mutations, which prevent AKT targeting and lock the transcription factor in the nucleus, are used by BL to circumvent mutual exclusivity between PI3K and FOXO1 activation. Using genome editing in human and mouse lymphomas in which MYC and PI3K cooperate synergistically in tumor development, we demonstrate proproliferative and antiapoptotic activity of FOXO1 in BL and identify its nuclear localization as an oncogenic event in GC B-cell-derived lymphomagenesis.
Asunto(s)
Linfocitos B , Linfoma de Burkitt , Núcleo Celular , Transformación Celular Neoplásica , Proteína Forkhead Box O1 , Centro Germinal , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Linfoma de Burkitt/genética , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patología , Línea Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Edición Génica , Centro Germinal/metabolismo , Centro Germinal/patología , Humanos , Ratones , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Interferon α (IFNα) is a prompt and efficient orchestrator of host defense against nucleic acids but upon chronicity becomes a potent mediator of autoimmunity. Sustained IFNα signaling is linked to pathogenesis of systemic lupus erythematosus (SLE), an incurable autoimmune disease characterized by aberrant self-DNA sensing that culminates in anti-DNA autoantibody-mediated pathology. IFNα instructs monocytes differentiation into autoinflammatory dendritic cells (DCs) than potentiates the survival and expansion of autoreactive lymphocytes, but the molecular mechanism bridging sterile IFNα-danger alarm with adaptive response against self-DNA remains elusive. Herein, we demonstrate IFNα-mediated deregulation of mitochondrial metabolism and impairment of autophagic degradation, leading to cytosolic accumulation of mtDNA that is sensed via stimulator of interferon genes (STING) to promote induction of autoinflammatory DCs. Identification of mtDNA as a cell-autonomous enhancer of IFNα signaling underlines the significance of efficient mitochondrial recycling in the maintenance of peripheral tolerance. Antioxidant treatment and metabolic rescue of autolysosomal degradation emerge as drug targets in SLE and other IFNα-related pathologies.
Asunto(s)
Autofagia/efectos de los fármacos , ADN Mitocondrial/metabolismo , Interferón-alfa/farmacología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/patología , Proteínas de la Membrana/metabolismo , Monocitos/inmunología , Adenosina Trifosfato/metabolismo , Adolescente , Adulto , Anciano , Autofagosomas/efectos de los fármacos , Autofagosomas/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Inflamación/patología , Receptores de Lipopolisacáridos/metabolismo , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Monocitos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Adulto JovenRESUMEN
Germinal centers (GC) are the predominant origin of human B cell lymphomagenesis. Transgenic mice in which gene expression is altered specifically in GC B cells have broadened our knowledge about the mechanisms of malignant transformation. However, extensive resources are needed due to the genetic complexity of these mouse models. Thus, bone marrow (BM)-derived chimerism is an attractive approach to study GC B cell derived lymphomagenesis, as it allows for an efficient allocation of resources and reduces the number of animals used.