RESUMEN
Coordinated recombination of homologous antigen receptor loci is thought to be important for allelic exclusion. Here we show that homologous immunoglobulin alleles pair in a stage-specific way that mirrors the recombination patterns of these loci. The frequency of homologous immunoglobulin pairing was much lower in the absence of the RAG-1-RAG-2 recombinase and was restored in Rag1-/- developing B cells with a transgene expressing a RAG-1 active-site mutant that supported DNA binding but not cleavage. The introduction of DNA breaks on one immunoglobulin allele induced ATM-dependent repositioning of the other allele to pericentromeric heterochromatin. ATM activated by the cleaved allele acts in trans on the uncleaved allele to prevent biallelic recombination and chromosome breaks or translocations.
Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Proteínas de Homeodominio/genética , Inmunoglobulinas/genética , Proteínas Serina-Treonina Quinasas/genética , Recombinación Genética , Proteínas Supresoras de Tumor/genética , Alelos , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Linfocitos B/metabolismo , Células Cultivadas , Roturas del ADN , Reordenamiento Génico , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , VDJ Recombinasas/metabolismoRESUMEN
A hallmark of the cellular response to DNA double-strand breaks (DSBs) is histone H2AX phosphorylation in chromatin to generate gamma-H2AX. Here, we demonstrate that gamma-H2AX densities increase transiently along DNA strands as they are broken and repaired in G1 phase cells. The region across which gamma-H2AX forms does not spread as DSBs persist; rather, gamma-H2AX densities equilibrate at distinct levels within a fixed distance from DNA ends. Although both ATM and DNA-PKcs generate gamma-H2AX, only ATM promotes gamma-H2AX formation to maximal distance and maintains gamma-H2AX densities. MDC1 is essential for gamma-H2AX formation at high densities near DSBs, but not for generation of gamma-H2AX over distal sequences. Reduced H2AX levels in chromatin impair the density, but not the distance, of gamma-H2AX formed. Our data suggest that H2AX fuels a gamma-H2AX self-reinforcing mechanism that retains MDC1 and activated ATM in chromatin near DSBs and promotes continued local phosphorylation of H2AX.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Daño del ADN , Proteínas de Unión al ADN/metabolismo , ADN/metabolismo , Histonas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Linfocitos B/citología , Linfocitos B/fisiología , Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Endonucleasas , Fase G1/fisiología , Genes Codificadores de la Cadena alfa de los Receptores de Linfocito T/genética , Histonas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Ratones Noqueados , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Recombinación Genética , Timo/citología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/genéticaRESUMEN
The ataxia telangiectasia mutated (ATM) kinase and H2AX histone tumor suppressor proteins are each critical for maintenance of cellular genomic stability and suppression of lymphomas harboring clonal translocations. ATM is the predominant kinase that phosphorylates H2AX in chromatin around DNA double-strand breaks, including along lymphocyte Ag receptor loci cleaved during V(D)J recombination. However, combined germline inactivation of Atm and H2ax in mice causes early embryonic lethality associated with substantial cellular genomic instability, indicating that ATM and H2AX exhibit nonredundant functions in embryonic cells. To evaluate potential nonredundant roles of ATM and H2AX in somatic cells, we generated and analyzed Atm-deficient mice with conditional deletion of H2ax in αß T-lineage lymphocytes. Combined Atm/H2ax inactivation starting in early-stage CD4(-)/CD8(-) thymocytes resulted in lower numbers of later-stage CD4(+)/CD8(+) thymocytes, but led to no discernible V(D)J recombination defect in G1 phase cells beyond that observed in Atm-deficient cells. H2ax deletion in Atm-deficient thymocytes also did not affect the incidence or mortality of mice from thymic lymphomas with clonal chromosome 14 (TCRα/δ) translocations. Yet, in vitro-stimulated Atm/H2ax-deficient splenic αß T cells exhibited a higher frequency of genomic instability, including radial chromosome translocations and TCRß translocations, compared with cells lacking Atm or H2ax. Collectively, our data demonstrate that both redundant and nonredundant functions of ATM and H2AX are required for normal recombination of TCR loci, proliferative expansion of developing thymocytes, and maintenance of genomic stability in cycling αß T-lineage cells.
Asunto(s)
Ataxia Telangiectasia/inmunología , Proteínas de Ciclo Celular/fisiología , Proteínas de Unión al ADN/fisiología , Histonas/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Subgrupos de Linfocitos T/inmunología , Proteínas Supresoras de Tumor/fisiología , Animales , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/patología , Proteínas de la Ataxia Telangiectasia Mutada , Ciclo Celular/genética , Ciclo Celular/inmunología , Proteínas de Ciclo Celular/deficiencia , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Proliferación Celular , Proteínas de Unión al ADN/deficiencia , Sitios Genéticos/inmunología , Inestabilidad Genómica/inmunología , Histonas/deficiencia , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteínas Serina-Treonina Quinasas/deficiencia , Receptores de Antígenos de Linfocitos T alfa-beta/biosíntesis , Recombinación Genética/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Proteínas Supresoras de Tumor/deficienciaRESUMEN
Lymphocyte antigen receptor gene assembly occurs through the process of V(D)J recombination, which is initiated when the RAG endonuclease introduces DNA DSBs at two recombining gene segments to form broken DNA coding end pairs and signal end pairs. These paired DNA ends are joined by proteins of the nonhomologous end-joining (NHEJ) pathway of DSB repair to form a coding joint and signal joint, respectively. RAG DSBs are generated in G1-phase developing lymphocytes, where they activate the ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases to orchestrate diverse cellular DNA damage responses including DSB repair. Paradoxically, although Atm and DNA-PKcs both function during coding joint formation, Atm appears to be dispensible for signal joint formation; and although some studies have revealed an activity for DNA-PKcs during signal joint formation, others have not. Here we show that Atm and DNA-PKcs have overlapping catalytic activities that are required for chromosomal signal joint formation and for preventing the aberrant resolution of signal ends as potentially oncogenic chromosomal translocations.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Cromosomas , Proteína Quinasa Activada por ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Ratones , Ratones SCIDRESUMEN
H2AX and Artemis each cooperate with p53 to suppress lymphoma. Germline H2ax(-/-)p53(-/-) mice die of T-cell receptor-ß(-) (TCR-ß(-)) thymic lymphomas with translocations and other lesions characteristic of human T-cell acute lymphoblastic leukemia. Here, we demonstrate that mice with inactivation of H2ax and p53 in thymocytes die at later ages to TCR-ß(-) or TCR-ß(+) thymic lymphomas containing a similar pattern of translocations as H2ax(-/-)p53(-/-) tumors. Germline Artemis(-/-) p53(-/-) mice die of lymphomas with antigen receptor locus translocations, whereas Artemis(-/-)H2ax(-/-)p53(-/-) mice die at earlier ages from multiple malignancies. We show here that Artemis(-/-) mice with p53 deletion in thymocytes die of TCR-ß(-) tumors containing Tcrα/δ translocations, other clonal translocations, or aneuploidy, as well as Notch1 mutations. Strikingly, Artemis(-/-) mice with H2ax and p53 deletion in thymocytes exhibited a lower rate of mortality from TCR-ß(-) tumors, which harbored significantly elevated levels of genomic instability. Our data reveal that the cellular origin of H2ax and p53 loss impacts the rate of mortality from and developmental stage of thymic lymphomas, and suggest that conditional deletion of tumor suppressor genes may provide more physiologic models for human lymphoid malignancies than germline inactivation.
Asunto(s)
Histonas/fisiología , Linfoma/patología , Eliminación de Secuencia , Neoplasias del Timo/patología , Proteína p53 Supresora de Tumor/fisiología , Animales , Southern Blotting , Western Blotting , Endonucleasas , Citometría de Flujo , Inestabilidad Genómica , Humanos , Hibridación Fluorescente in Situ , Linfoma/etiología , Linfoma/metabolismo , Ratones , Ratones Noqueados , Proteínas Nucleares/fisiología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Linfocitos T/metabolismo , Timo/citología , Timo/metabolismo , Neoplasias del Timo/etiología , Neoplasias del Timo/metabolismo , Translocación GenéticaRESUMEN
This paper presents a computational study of the adsorptive desulfurization of small aromatic sulfur compounds by conjugated microporous polymers (CMPs). The density-functional tight-binding method augmented with an R-6 dispersion correction is employed to investigate the physisorption binding mechanism and electronic properties of the CMP-aromatic sulfur complexes. We show that the widely extended π conjugation in the CMP skeletons is favorable for the non-covalent adsorption of aromatic thiophene and dibenzothiophene via π-π, H-π, and S-π interactions. The average binding energies are calculated to be -6.2 â¼ -15.2 kcal/mol for CMP- thiophene/dibenzothiophene systems. For the dibenzothiophene molecule with larger size and more extended conjugation, it binds more than twice stronger to CMP than the thiophene molecule. We show that the replacement of quinoline unit to the phenylene group in the network linker effectively enhances the average binding capacities by around 0.8-1.8 kcal/mol. Our calculations theoretically demonstrate that CMPs materials are kind of promising candidates for the adsorptive desulfurization of small aromatic sulfur compounds. This paper provides useful theoretical guidance for design of novel carbon-based adsorbents for adsorptive desulfurization.
Asunto(s)
Polímeros , Azufre , Adsorción , Compuestos de AzufreRESUMEN
DNA double strand breaks (DSBs) induced during cellular metabolism, DNA replication, and genomic rearrangement events lead to phosphorylation of the H2AX core histone variant in surrounding chromatin. H2AX is essential for normal DSB repair, maintenance of genomic stability, and suppression of lymphomas with clonal translocations and intra-chromosomal deletions. One current focus of our lab is to elucidate mechanisms through which H2AX functions in the cellular DNA damage response using V(D)J recombination as a model system. A number of potential H2AX functions can be readily tested using novel experimental approaches developed in our lab. These putative functions include: (1) modulation of chromatin accessibility to facilitate kinetics of DSB repair, (2) stabilization of broken DNA strands to maintain ends in close proximity, and (3) amplification of DNA damage signals. Here, we summarize our recent efforts in elucidating mechanisms by which H2AX functions during V(D)J recombination to coordinate DSB repair with cellular proliferation and survival to prevent translocations and suppress lymphomagenesis.
Asunto(s)
Inestabilidad Genómica , Histonas/fisiología , Región Variable de Inmunoglobulina/genética , Linfoma/patología , Animales , Roturas del ADN de Doble Cadena , Reparación del ADN , Reordenamiento Génico , HumanosRESUMEN
The DNA damage response (DDR) can restrain the ability of oncogenes to cause genomic instability and drive malignant transformation. The gene encoding the histone H2AX DDR factor maps to 11q23, a region frequently altered in human cancers. Since H2ax functions as a haploinsufficient suppressor of B lineage lymphomas with c-Myc amplification and/or translocation, we determined the impact of H2ax expression on the ability of deregulated c-Myc expression to cause genomic instability and drive transformation of B cells. Neither H2ax deficiency nor haploinsufficiency affected the rate of mortality of Eµ-c-Myc mice from B lineage lymphomas with genomic deletions and amplifications. Yet H2ax functioned in a dosage-dependent manner to prevent unbalanced translocations in Eµ-c-Myc tumors, demonstrating that H2ax functions in a haploinsufficient manner to suppress allelic imbalances and limit molecular heterogeneity within and among Eµ-c-Myc lymphomas. Regardless of H2ax copy number, all Eµ-c-Myc tumors contained identical amplification of chromosome 19 sequences spanning 20 genes. Many of these genes encode proteins with tumor-promoting activities, including Cd274, which encodes the PD-L1 programmed death ligand that induces T cell apoptosis and enables cancer cells to escape immune surveillance. This amplicon was in non-malignant B and T cells and non-lymphoid cells, linked to the Eµ-c-Myc transgene, and associated with overexpression of PD-L1 on non-malignant B cells. Our data demonstrate that, in addition to deregulated c-Myc expression, non-malignant B lineage lymphocytes of Eµ-c-Myc transgenic mice may have constitutive amplification and increased expression of other tumor-promoting genes.
Asunto(s)
Células Germinativas/metabolismo , Histonas/metabolismo , Linfoma/genética , Oncogenes/genética , Proteínas Proto-Oncogénicas c-myc/genética , Translocación Genética , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Linaje de la Célula/genética , Cromosomas de los Mamíferos/metabolismo , Células Clonales , Hibridación Genómica Comparativa , Amplificación de Genes/genética , Eliminación de Gen , Haploinsuficiencia/genética , Humanos , Linfoma/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Supresión Genética , Transgenes/genéticaRESUMEN
Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that plays important regulatory roles in several basic cellular activities. During normal development, FAK is a critical mediator of the integrin signaling cascade, which modulates cell proliferation, apoptosis, adhesion, spreading and migration. Importantly, FAK overexpression is found in a large number of cancer types and FAK expression levels generally correlate with increased tumor malignancy. Though FAK has been a popular potential target for treatment of solid tumors, its roles in leukemias and lymphomas have not been well defined. Here, I briefly summarize the multifaceted functions of FAK in tumor progression, and discuss current efforts and exciting future directions of using RNAi-mediated knockdown of FAK as a potential therapy against leukemia and lymphomas.
Asunto(s)
Proteína-Tirosina Quinasas de Adhesión Focal , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , ARN Interferente Pequeño/farmacología , Transducción de Señal , Apoptosis/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Silenciador del Gen/efectos de los fármacos , Humanos , Integrinas/genética , Integrinas/metabolismo , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologíaRESUMEN
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
RESUMEN
Mutations in the tumor-suppressor gene phosphatase and tensin homolog deleted on chromosome 10 (Pten) are associated with multiple cancers in humans, including T cell malignancies. Targeted deletion of Pten in T cells induces both a disseminated "mature phenotype" lymphoma and a lymphoproliferative autoimmune syndrome in mice. Here, we have shown that these two diseases are separable and mediated by T lineage cells of distinct developmental stages. Loss of PTEN was found to be a powerful driver of lymphomagenesis within the thymus characterized by overexpression of the c-myc oncogene. In an otherwise normal thymic environment, PTEN-deficient T cell lymphomas invariably harbored RAG-dependent reciprocal t(14:15) chromosomal translocations involving the T cell receptor alpha/delta locus and c-myc, and their survival and growth was TCR dependent, but Notch independent. However, lymphomas occurred even if TCR recombination was prevented, although these lymphomas were less mature, arose later in life, and, importantly, were dependent upon Notch pathways to upregulate c-myc expression. In contrast, using the complementary methods of early thymectomy and adoptive transfers, we found that PTEN-deficient mature T cells were unable to undergo malignant transformation but were sufficient for the development of autoimmunity. These data suggest multiple and distinct regulatory roles for PTEN in the molecular pathogenesis of lymphoma and autoimmunity.
Asunto(s)
Linfoma de Células T/genética , Linfoma de Células T/patología , Linfoma/genética , Animales , Síndrome Linfoproliferativo Autoinmune , Genes , Humanos , Linfoma/metabolismo , Linfoma de Células T/metabolismo , Ratones , Ratones Noqueados , Mutación , Neoplasias/genética , Neoplasias/metabolismo , Fosfohidrolasa PTEN , Fenotipo , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Eliminación de Secuencia , Timo/metabolismo , Timo/patología , Translocación GenéticaRESUMEN
Chromosomal abnormalities are frequently caused by problems encountered during DNA replication. Although the ATR-Chk1 pathway has previously been implicated in preventing the collapse of stalled replication forks into double-strand breaks (DSB), the importance of the response to fork collapse in ATR-deficient cells has not been well characterized. Herein, we demonstrate that, upon stalled replication, ATR deficiency leads to the phosphorylation of H2AX by ATM and DNA-PKcs and to the focal accumulation of Rad51, a marker of homologous recombination and fork restart. Because H2AX has been shown to play a facilitative role in homologous recombination, we hypothesized that H2AX participates in Rad51-mediated suppression of DSBs generated in the absence of ATR. Consistent with this model, increased Rad51 focal accumulation in ATR-deficient cells is largely dependent on H2AX, and dual deficiencies in ATR and H2AX lead to synergistic increases in chromatid breaks and translocations. Importantly, the ATM and DNA-PK phosphorylation site on H2AX (Ser(139)) is required for genome stabilization in the absence of ATR; therefore, phosphorylation of H2AX by ATM and DNA-PKcs plays a pivotal role in suppressing DSBs during DNA synthesis in instances of ATR pathway failure. These results imply that ATR-dependent fork stabilization and H2AX/ATM/DNA-PKcs-dependent restart pathways cooperatively suppress double-strand breaks as a layered response network when replication stalls.
Asunto(s)
Proteínas de Ciclo Celular/fisiología , Roturas del ADN de Doble Cadena , Replicación del ADN , Inestabilidad Genómica , Histonas/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Proteína Quinasa Activada por ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Embrión de Mamíferos/efectos de la radiación , Fibroblastos/citología , Fibroblastos/metabolismo , Fibroblastos/efectos de la radiación , Metafase , Ratones , Ratones Noqueados , Mitosis , Proteínas Nucleares/metabolismo , Fosforilación , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/farmacología , Recombinasa Rad51/metabolismo , Radiación Ionizante , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Fase S/fisiología , Cariotipificación Espectral , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Large homozygous deletions of 9p21 that inactivate CDKN2A, ARF, and MTAP are common in a wide variety of human cancers. The role for CDKN2A and ARF in tumorigenesis is well established, but whether MTAP loss directly affects tumorigenesis is unclear. MTAP encodes the enzyme methylthioadenosine phosphorylase, a key enzyme in the methionine salvage pathway. To determine if loss of MTAP plays a functional role in tumorigenesis, we have created an MTAP-knockout mouse. Mice homozygous for a MTAP null allele (Mtap(lacZ)) have an embryonic lethal phenotype dying around day 8 postconception. Mtap/Mtap(lacZ) heterozygotes are born at Mendelian frequencies and appear indistinguishable from wild-type mice during the first year of life, but they tend to die prematurely with a median survival of 585 days. Autopsies on these animals reveal that they have greatly enlarged spleens, altered thymic histology, and lymphocytic infiltration of their livers, consistent with lymphoma. Immunohistochemical staining and fluorescence-activated cell sorting analysis indicate that these lymphomas are primarily T-cell in origin. Lymphoma-infiltrated tissues tend to have reduced levels of Mtap mRNA and MTAP protein in addition to unaltered levels of methyldeoxycytidine. These studies show that Mtap is a tumor suppressor gene independent of CDKN2A and ARF.
Asunto(s)
Mutación de Línea Germinal , Linfoma de Células T/genética , Purina-Nucleósido Fosforilasa/genética , Animales , Complejo CD3/análisis , Relación CD4-CD8 , Hibridación Genómica Comparativa , Desoxicitidina/metabolismo , Embrión de Mamíferos/embriología , Embrión de Mamíferos/metabolismo , Femenino , Citometría de Flujo , Heterocigoto , Homocigoto , Inmunohistoquímica , Antígenos Comunes de Leucocito/análisis , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Linfoma de Células T/mortalidad , Linfoma de Células T/patología , Masculino , Metilación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Embarazo , Purina-Nucleósido Fosforilasa/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
The H2AX core histone variant is phosphorylated in chromatin around DNA double strand breaks (DSBs) and functions through unknown mechanisms to suppress antigen receptor locus translocations during V(D)J recombination. Formation of chromosomal coding joins and suppression of translocations involves the ataxia telangiectasia mutated and DNA-dependent protein kinase catalytic subunit serine/threonine kinases, each of which phosphorylates H2AX along cleaved antigen receptor loci. Using Abelson transformed pre-B cell lines, we find that H2AX is not required for coding join formation within chromosomal V(D)J recombination substrates. Yet we show that H2AX is phosphorylated along cleaved Igkappa DNA strands and prevents their separation in G1 phase cells and their progression into chromosome breaks and translocations after cellular proliferation. We also show that H2AX prevents chromosome breaks emanating from unrepaired RAG endonuclease-generated TCR-alpha/delta locus coding ends in primary thymocytes. Our data indicate that histone H2AX suppresses translocations during V(D)J recombination by creating chromatin modifications that stabilize disrupted antigen receptor locus DNA strands to prevent their irreversible dissociation. We propose that such H2AX-dependent mechanisms could function at additional chromosomal locations to facilitate the joining of DNA ends generated by other types of DSBs.
Asunto(s)
Cromatina/metabolismo , Rotura Cromosómica , Roturas del ADN de Doble Cadena , Histonas/metabolismo , Recombinación Genética/fisiología , Exones VDJ/fisiología , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Linfocitos B/inmunología , Linfocitos B/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/inmunología , Proteínas de Ciclo Celular/metabolismo , Línea Celular Transformada , Cromatina/genética , Cromatina/inmunología , Fase G1/fisiología , Histonas/genética , Histonas/inmunología , Ratones , Ratones Noqueados , Fosforilación/fisiología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Sitios de Carácter Cuantitativo/fisiología , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismoRESUMEN
Ataxia telangiectasia (A-T) is a disorder characterized by cerebellar degeneration, immunodeficiency, genomic instability and genetic predisposition to lymphoid malignancies with translocations involving antigen receptor loci. The Ataxia Telangiectasia Mutated gene encodes the ATM kinase, a central transducer of DNA damage signals. Until recently, the etiology of the lymphoid phenotype in A-T patients and the mechanisms by which ATM ensures normal repair of DNA double strand break (DSB) intermediates during antigen receptor diversification reactions remained poorly understood. Last year, Bredemeyer et al. (Nature 2006; 442:466-70) demonstrated that ATM stabilizes chromosomal V(D)J recombination DSB intermediates, facilitates DNA end joining and prevents broken DNA ends from participating in chromosome deletions, inversions and translocations. A more recent study by Callen et al. (Cell 2007; 130:63-75) highlighted the importance of ATM-mediated checkpoints in blocking the long-term persistence and transmission of un-repaired DSBs in developing lymphocytes. Collectively, these results have provided complementary mechanistic insights into ATM functions in V(D)J recombination that can account for the lymphoid tumor-prone phenotype associated with A-T.