Centromere identity and function is determined by the specific localization of CenH3 (reviewed in 1-7). Several mechanisms regulate centromeric CenH3 localization, including proteasome-mediated ...degradation that, both in budding yeast and Drosophila, regulates CenH3 levels and prevents promiscuous misincorporation throughout chromatin 8, 9. CenH3(CENP-A) proteolysis has also been reported in senescent human cells 10 or upon infection with herpes simplex virus 1 11. Little is known, however, about the actual mechanisms that regulate CenH3 proteolysis. Recent work in budding yeast identified Psh1 as an E3-ubiquitin ligase that mediates degradation of CenH3(Cse4p) 12, 13, but E3-ligases regulating CenH3 stability in metazoans are unknown. Here, we report that the F box protein partner of paired (Ppa), which is a variable subunit of the main E3-ligase SCF 14-17, mediates CenH3(CID) stability in Drosophila. Our results show that Ppa depletion results in increased CenH3(CID) levels. Ppa physically interacts with CenH3(CID) through the CATD(CID) that, in the fly, mediates Ppa-dependent CenH3(CID) stability. Altogether, these results strongly suggest that, in Drosophila, SCF(Ppa) regulates CenH3(CID) proteolysis. Interestingly, most known SCF complexes are inactive when, at mitosis, de novo CenH3(CID) deposition takes place at centromeres, suggesting that, in Drosophila, CenH3(CID) deposition and proteolysis are synchronized events.
Centromere identity is determined epigenetically by deposition of CenH3, a centromere-specific histone H3 variant that dictates kinetochore assembly. The molecular basis of the contribution of CenH3 ...to centromere/kinetochore functions is, however, incompletely understood, as its interactions with the rest of centromere/kinetochore components remain largely uncharacterised at the molecular/structural level.
Here, we report on the contribution of Drosophila CenH3(CID) to recruitment of BubR1, a conserved kinetochore protein that is a core component of the spindle attachment checkpoint (SAC). This interaction is mediated by the N-terminal domain of CenH3(CID) (NCenH3(CID)), as tethering NCenH3(CID) to an ectopic reporter construct results in BubR1 recruitment and BubR1-dependent silencing of the reporter gene. Here, we also show that this interaction depends on a short arginine (R)-rich motif and that, most remarkably, it appears to be evolutionarily conserved, as tethering constructs carrying the highly divergent NCenH3 of budding yeast and human also induce silencing of the reporter. Interestingly, though NCenH3 shows an exceedingly low degree of conservation, the presence of R-rich motives is a common feature of NCenH3 from distant species. Finally, our results also indicate that two other conserved sequence motives within NCenH3(CID) might also be involved in interactions with kinetochore components.
These results unveil an unexpected contribution of the hypervariable N-domain of CenH3 to recruitment of kinetochore components, identifying simple R-rich motives within it as evolutionary conserved structural determinants involved in BubR1 recruitment.
Barrier-to-Autointegration Factor (BAF) is a conserved nuclear envelope (NE) component that binds chromatin and helps its anchoring to the NE. Cycles of phosphorylation and dephosphorylation control ...BAF function. Entering mitosis, phosphorylation releases BAF from chromatin and facilitates NE-disassembly. At mitotic exit, PP2A-mediated dephosphorylation restores chromatin binding and nucleates NE-reassembly. Here, we show that in Drosophila a small fraction of BAF (cenBAF) associates with centromeres. We also find that PP4 phosphatase, which is recruited to centromeres by CENP-C, prevents phosphorylation and release of cenBAF during mitosis. cenBAF is necessary for proper centromere assembly and accurate chromosome segregation, being critical for mitosis progression. Disrupting cenBAF localization prevents PP2A inactivation in mitosis compromising global BAF phosphorylation, which in turn leads to its persistent association with chromatin, delays anaphase onset and causes NE defects. These results suggest that, together with PP4 and CENP-C, cenBAF forms a centromere-based mechanism that controls chromosome segregation and mitosis progression.
Centromere identity and function is determined by the specific localization of CenH3 (reviewed in 1, 2, 3, 4, 5, 6 and 7). Several mechanisms regulate centromeric CenH3 localization, including ...proteasome-mediated degradation that, both in budding yeast and Drosophila, regulates CenH3 levels and prevents promiscuous misincorporation throughout chromatin 8 and 9. CenH3 super(CENP-A) proteolysis has also been reported in senescent human cells 12 and 13, but E3-ligases regulating CenH3 stability in metazoans are unknown. Here, we report that the F box protein partner of paired (Ppa), which is a variable subunit of the main E3-ligase SCF 14, 15, 16 and 17, mediates CenH3 super(CID) stability in Drosophila. Our results show that Ppa depletion results in increased CenH3 super(CID) levels. Ppa physically interacts with CenH3 super(CID) through the CATD super(CID) that, in the fly, mediates Ppa-dependent CenH3 super(CID) stability. Altogether, these results strongly suggest that, in Drosophila, SCF super(Ppa) regulates CenH3 super(CID) proteolysis. Interestingly, most known SCF complexes are inactive when, at mitosis, de novo CenH3 super(CID) deposition takes place at centromeres, suggesting that, in Drosophila, CenH3 super(CID) deposition and proteolysis are synchronized events.
Centromere identity and function is determined by the specific localization of CenH3 (reviewed in
1–7). Several mechanisms regulate centromeric CenH3 localization, including proteasome-mediated ...degradation that, both in budding yeast and
Drosophila, regulates CenH3 levels and prevents promiscuous misincorporation throughout chromatin
8, 9. CenH3
CENP-A proteolysis has also been reported in senescent human cells
10 or upon infection with herpes simplex virus 1
11. Little is known, however, about the actual mechanisms that regulate CenH3 proteolysis. Recent work in budding yeast identified Psh1 as an E3-ubiquitin ligase that mediates degradation of CenH3
Cse4p
12, 13, but E3-ligases regulating CenH3 stability in metazoans are unknown. Here, we report that the F box protein partner of paired (Ppa), which is a variable subunit of the main E3-ligase SCF
14–17, mediates CenH3
CID stability in
Drosophila. Our results show that Ppa depletion results in increased CenH3
CID levels. Ppa physically interacts with CenH3
CID through the CATD
CID that, in the fly, mediates Ppa-dependent CenH3
CID stability. Altogether, these results strongly suggest that, in
Drosophila, SCF
Ppa regulates CenH3
CID proteolysis. Interestingly, most known SCF complexes are inactive when, at mitosis, de novo CenH3
CID deposition takes place at centromeres, suggesting that, in
Drosophila, CenH3
CID deposition and proteolysis are synchronized events.
► The SCF component partner of paired mediates CenH3
CID stability in
Drosophila ► Ppa physically interacts with CenH3
CID through the CATD
CID ► CATD
CID mediates Ppa-dependent CenH3
CID stability
Centromere identity is determined epigenetically by deposition of CenH3, a centromere-specific histone H3 variant that dictates kinetochore assembly. The molecular basis of the contribution of CenH3 ...to centromere/kinetochore functions is, however, incompletely understood, as its interactions with the rest of centromere/kinetochore components remain largely uncharacterised at the molecular/structural level. These results unveil an unexpected contribution of the hypervariable N-domain of CenH3 to recruitment of kinetochore components, identifying simple R-rich motives within it as evolutionary conserved structural determinants involved in BubR1 recruitment.
Antecedentes: la Anemia de Fanconi (AF) es una enfermedad heredada, que afecta la reparación del ADN. Clínicamente es heterogénea; mayoritariamente se presentan malformaciones congénitas, aplasia ...medular temprana y predisposición a cáncer. El defecto genético causa hipersensibilidad a genotóxicos e inestabilidad cromosómica. Esta característica se considera el mejor marcador diagnóstico; sin embargo, llegar a él puede convertirse en un desafío. Objetivo: caracterizar pacientes con AF mediante pruebas citogenéticas en individuos con rasgos clínicos sugestivos de la enfermedad. Métodos: se analizaron 157 individuos con sospecha clínica de AF, 19 con asociación VACTERL, 15 hermanos, y 34 individuos sanos. Se realizó registro de datos clínicos, y prueba citogenética con Diepoxibutano (DEB). Resultados: se identificaron 43 afectados por AF. La relación de índices en células tratadas con DEB del grupo AF vs. No-AF fue significativamente incrementada, 6.7 veces la proporción de células aberrantes, 48 veces el número de roturas por célula, y 6.3 veces el número de roturas por célula aberrante. En AF la edad media de muestreo fue 9.2 años, la proporción de sexos M:F 1.5:1, consanguinidad en 11 casos. Los sistemas hematológico, esquelético, tegumentario, y urinario estuvieron significativamente alterados. Conclusiones: La AF se identificó en 26 % del grupo de sospecha y en 13 % de hermanos sin sospecha previa. La enfermedad hematológica fue el síntoma más recurrente presente en 93 % de los casos, y fue principalmente la primera sospecha de AF y motivo de estudio genético.
A consecuencia de los cambios climáticos suscitados hasta la actualidad, una visión ambientalista ha venido tomando posición en el mundo acerca de la educación ambiental. Frente a esto, el objetivo ...general del presente estudio es analizar la influencia de la educación ambiental en la formación integral de los estudiantes de la Educación Básica Regular. Seguidamente, los procedimientos que se realizaron en la construcción del estudio consistió en la identificación, clasificación y selección de diversas investigaciones de Latinoamérica, Oceanía, Europa y Asia, que abordan contenidos relacionados a la educación ambiental y la formación integral de estudiantes de educación primaria. Por tal motivo, el enfoque es cualitativo, porque responde a un estudio documental desarrollado desde el método revisión de la literatura. Finalmente, los resultados obtenidos en la investigación son los siguientes, sí existe una influencia directa entre la educación ambiental y el ámbito educativo, se evidencia la existencia de una relación directa entre la educación ambiental con la formación integral y la educación ambiental influye en la formación integral de los estudiantes de primaria, es decir, estos resultados son producto de la relación directa que el estudiante mantiene con el medio ambiente en su proceso constante de construcción del aprendizaje.
Se presentan las conclusiones consensuadas de un panel de arritmólogos, convocados por la Sociedad Española de Cardiología, acerca del enfoque terapéutico de las arritmias cardíacas. El manuscrito se ...ha dividido en 7 secciones, que representan áreas de afinidad en cuanto a terapéutica:
1. Taquicardias supraventriculares no asociadas al síndrome de Wolff-Parkinson-White.
2. Síndromes de preexcitación.
3. Flúter auricular.
4. Fibrilación auricular.
5. Arritmias ventriculares no sostenidas.
6. Taquicardias ventriculares sostenidas (en ausenciade síndrome de parada cardíaca).
7. Síndrome de parada cardíaca por taquiarritmia ventricular.
En cada una de las secciones se emiten recomendaciones en cuanto a las distintas opciones terapéuticas, farmacológicas y no farmacológicas, así como en cuanto a los subgrupos de pacientes subsidiarios de cada una de ellas.
We present the conclusions of a panel of arrhythmologists joint by the Spanish Society of Cardiology to achieve a consensus regarding the current approach to therapy of cardiac arrhythmias. The manuscript has been divided into 7 sections, selected by therapeutic affinity:
1. Supraventricular tachyarrhythmias not associated with the Wolff-Parkinson-White syndrome.
2. Preexcitation syndromes.
3. Atrial flutter.
4. Atrial fibrillation.
5. Non sustained ventricular arrhythmias.
6. Sustained ventricular tachycardia (in the absence of cardiac arrest).
7. Syndrome of cardiac arrest due to ventricular tachyarrhythmia.
On each section, recommendations regarding pharmacologic and/or non pharmacologic therapeutic options are generated; in addition, we describe patient subgroups candidates to each form of therapy.
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