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RNF8 transduce la señal de daño en el ADN a través de la ubicuidad de histonas y el ensamblaje de proteínas de punto
Michael S Y Huen1, Robert Grant, Isaac Manke
1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell
|November 16, 2007
Resumen
RNF8 es crucial para la respuesta temprana al daño del ADN, ayudando en la acumulación de proteínas de punto de control y la reparación del ADN. Las células que carecen de RNF8 muestran deterioro de los puntos de control del ciclo celular y una mayor sensibilidad al daño del ADN.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
- La bioquímica es la bioquímica.
Sus antecedentes:
- La respuesta al daño en el ADN (DDR, por sus siglas en inglés) implica modificaciones post-traduccionales.
- Los puntos de control del ciclo celular, la reparación del ADN, la senescencia y la apoptosis están regulados por el DDR.
Objetivo del estudio:
- Para investigar el papel de RNF8 en la respuesta temprana al daño del ADN.
- Para dilucidar los mecanismos moleculares por los cuales las funciones de RNF8 en DDR.
Principales métodos:
- Cristalografía de rayos X para determinar la estructura del dominio FHA de RNF8.8.
- Análisis celulares para evaluar el impacto del agotamiento de RNF8 en las vías de respuesta al daño del ADN.
- Análisis de las interacciones proteína-proteína y eventos de ubicuidad.
Principales resultados:
- RNF8 facilita el reclutamiento de BRCA1 y 53BP1 a la cromatina dañada.
- RNF8 se une a MDC1 de manera fosfodependiente a través de su dominio FHA.
- RNF8 ubiquitinates H2AX y otros sustratos en los sitios de daño del ADN.
- Las células empobrecidas de RNF8 exhiben un punto de control G2/M defectuoso y una mayor sensibilidad a la radiación ionizante (IR).
Conclusiones:
- RNF8 es una nueva proteína sensible al daño del ADN.
- RNF8 integra la señalización de fosforilación y ubicuidad en DDR.
- RNF8 juega un papel crítico en la respuesta celular al estrés genotóxico.
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