RESUMEN
Evolutionary forces that shape regulatory networks remain poorly understood. In mammals, the Rb pathway is a classic example of species-specific gene regulation, as a germline mutation in one Rb allele promotes retinoblastoma in humans, but not in mice. Here we show that p53 transactivates the Retinoblastoma-like 2 (Rbl2) gene to produce p130 in murine, but not human, cells. We found intronic fuzzy tandem repeats containing perfect p53 response elements to be important for this regulation. We next identified two other murine genes regulated by p53 via fuzzy tandem repeats: Ncoa1 and Klhl26. The repeats are poorly conserved in evolution, and the p53-dependent regulation of the murine genes is lost in humans. Our results indicate a role for the rapid evolution of tandem repeats in shaping differences in p53 regulatory networks between mammalian species.
Asunto(s)
Regulación de la Expresión Génica , Proteína p130 Similar a la del Retinoblastoma , Retinoblastoma/genética , Secuencias Repetidas en Tándem/genética , Proteína p53 Supresora de Tumor , Animales , Células Cultivadas , Evolución Molecular , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Intrones/genética , Ratones , Mutación , Coactivador 1 de Receptor Nuclear/genética , Coactivador 1 de Receptor Nuclear/metabolismo , Elementos de Respuesta/genética , Proteína p130 Similar a la del Retinoblastoma/genética , Proteína p130 Similar a la del Retinoblastoma/metabolismo , Especificidad de la Especie , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The mechanisms governing telomere replication in humans are still poorly understood. To fill this gap, we investigated the timing of replication of single telomeres in human cells. Using in situ hybridization techniques, we have found that specific telomeres have preferential time windows for replication during the S-phase and that these intervals do not depend upon telomere length and are largely conserved between homologous chromosomes and between individuals, even in the presence of large subtelomeric segmental polymorphisms. Importantly, we show that one copy of the 3.3 kb macrosatellite repeat D4Z4, present in the subtelomeric region of the late replicating 4q35 telomere, is sufficient to confer both a more peripheral localization and a later-replicating property to a de novo formed telomere. Also, the presence of beta-satellite repeats next to a newly created telomere is sufficient to delay its replication timing. Remarkably, several native, non-D4Z4-associated, late-replicating telomeres show a preferential localization toward the nuclear periphery, while several early-replicating telomeres are associated with the inner nuclear volume. We propose that, in humans, chromosome arm-specific subtelomeric sequences may influence both the spatial distribution of telomeres in the nucleus and their replication timing.
Asunto(s)
Núcleo Celular/metabolismo , Replicación del ADN , Telómero/química , Línea Celular , Cromosomas/metabolismo , Humanos , Fase S , Telomerasa/metabolismo , Telómero/metabolismo , Proteínas de Unión a Telómeros/metabolismoRESUMEN
Atypical teratoid rhabdoid tumors (ATRT) are divided into MYC, TYR and SHH subgroups, suggesting diverse lineages of origin. Here, we investigate the imaging of human ATRT at diagnosis and the precise anatomic origin of brain tumors in the Rosa26-CreERT2::Smarcb1flox/flox model. This cross-species analysis points to an extra-cerebral origin for MYC tumors. Additionally, we clearly distinguish SHH ATRT emerging from the cerebellar anterior lobe (CAL) from those emerging from the basal ganglia (BG) and intra-ventricular (IV) regions. Molecular characteristics point to the midbrain-hindbrain boundary as the origin of CAL SHH ATRT, and to the ganglionic eminence as the origin of BG/IV SHH ATRT. Single-cell RNA sequencing on SHH ATRT supports these hypotheses. Trajectory analyses suggest that SMARCB1 loss induces a de-differentiation process mediated by repressors of the neuronal program such as REST, ID and the NOTCH pathway.
Asunto(s)
Neoplasias Encefálicas , Tumor Rabdoide , Teratoma , Humanos , Tumor Rabdoide/genética , Multiómica , Proteína SMARCB1/genética , Factores de Transcripción/genética , Neoplasias Encefálicas/genética , Diagnóstico por Imagen , Teratoma/patología , Proteínas Hedgehog/genéticaRESUMEN
The clinical importance of tumor suppressor p53 makes it one of the most studied transcription factors. A comparison of mammalian p53 transcriptional repertoires may help identify fundamental principles in genome evolution and better understand cancer processes. Here we summarize mechanisms underlying the divergence of mammalian p53 transcriptional repertoires, with an emphasis on the rapid evolution of fuzzy tandem repeats containing p53 response elements.
Asunto(s)
Proteína p53 Supresora de Tumor/metabolismo , Animales , Evolución Molecular , Humanos , Ratones , Motivos de Nucleótidos , Regiones Promotoras Genéticas , Elementos de Respuesta , Proteína p130 Similar a la del Retinoblastoma/metabolismo , Secuencias Repetidas en Tándem , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Mutations in p53, although frequent in human cancers, have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53Δ31, a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres. Indeed, p53Δ31/Δ31 mice had short telomeres and other phenotypic traits associated with the telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson syndrome. Heterozygous p53+/Δ31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms. Importantly, several genes involved in telomere metabolism were downregulated in p53Δ31/Δ31 cells, including Dyskerin, Rtel1, and Tinf2, which are mutated in dyskeratosis congenita, and Terf1, which is implicated in aplastic anemia. Together, these data reveal that a truncating mutation can activate p53 and that p53 plays a major role in the regulation of telomere metabolism.