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A Cul4 E3 ubiquitin ligasa regula la transferencia de histonas durante el ensamblaje de los nucleosomas
Junhong Han1, Hui Zhang, Honglian Zhang
1Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
Cell
|November 12, 2013
Resumen
La histona acompañante Asf1 se une a las H3-H4.4 recién sintetizadas. Una ligasa E3 conservada se dirige al H3 acetilado para la ubicuidad, facilitando la transferencia de H3-H4 y el ensamblaje del nucleosoma. Esto revela un cruce entre la acetilación de histonas y la ubicuidad.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- La epigenética es la epigenética.
- Biología de la cromatina Biología de la cromatina
Sus antecedentes:
- El ensamblaje de los nucleosomas es crucial para la estabilidad del genoma y la herencia epigenética después de la replicación y transcripción del ADN.
- Las chaperonas de histonas, incluida la Asf1, administran las histonas recién sintetizadas H3-H4.4.
- El mecanismo de transferencia de H3-H4 de Asf1 a otras chaperonas sigue sin estar claro debido a la alta afinidad de Asf1.
Objetivo del estudio:
- Para investigar el mecanismo que regula la transferencia de H3-H4 desde el complejo chaperón Asf1.
- Identificar los factores que median la liberación de H3-H4 para el ensamblaje del nucleosoma.
- Para explorar la interacción entre la acetilación de histonas y la ubicuidad en este proceso.
Principales métodos:
- Se utilizaron modelos de levadura para estudiar la Rtt101(Mms1) E3 ubiquitina ligasa.
- Investigó la unión y ubicuidad de la histona H3, específicamente acetilada en la lisina 56.
- Empleó la inactivación genética y la mutagénesis dirigida al sitio de Rtt101 y H3.
- Se examinó la eficiencia del ensamblaje de nucleosomas y las interacciones Asf1-H3.
- Encontros corroborados en células humanas utilizando el agotamiento de Cul4A(DDB1).
Principales resultados:
- La levadura Rtt101(Mms1) E3 ubiquitina ligasa se une específicamente y ubicuita la histona H3 recientemente sintetizada acetilada en la lisina 56.
- La inactivación de Rtt101 o la mutación de los sitios de ubicuidad en H3 perjudica el ensamblaje del nucleosoma.
- Estas alteraciones genéticas también mejoran la interacción entre Asf1 y H3.
- Se observaron defectos similares en el ensamblaje de los nucleosomas e interacciones alteradas de las chaperonas en células humanas que carecían de Cul4A(DDB1).
Conclusiones:
- Una ligasa E3 conservada (Rtt101 (((Mms1) / Cul4A ((DDB1)) regula la transferencia de H3-H4 desde el complejo chaperón Asf1.
- La ubicuidad de la histona H3, particularmente en K56, es un paso clave para facilitar esta transferencia.
- Demuestra el cruce entre la acetilación de histonas y la ubicuidad en la regulación del ensamblaje del nucleosoma y el mantenimiento epigenético.
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