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La activación del ATM por el estrés oxidativo
Zhi Guo1, Sergei Kozlov, Martin F Lavin
1Howard Hughes Medical Institute, Department of Molecular Genetics and Microbiology, and Institute for Cellular and Molecular Biology (ICMB), University of Texas at Austin, Austin, TX 78712, USA.
Science (New York, N.Y.)
|October 23, 2010
Resumen
La oxidación activa directamente la proteína quinasa ataxia-telangiectasia mutada (ATM), independientemente del daño en el ADN. Este descubrimiento revela el ATM como un sensor clave del estrés oxidativo y las especies reactivas de oxígeno en las células humanas.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- La señalización celular.
Sus antecedentes:
- La proteína quinasa ataxia-telangiectasia mutada (ATM) es un regulador clave de la respuesta al daño del ADN, activada principalmente por rupturas de doble cadena de ADN (DSB) a través del complejo Mre11-Rad50-Nbs1 (MRN).
- Las células deficientes de ATM exhiben hipersensibilidad a varios insultos celulares, incluido el estrés oxidativo, lo que sugiere roles más allá de la reparación de DSB.
Objetivo del estudio:
- Investigar el mecanismo de activación directa de ATM bajo condiciones de estrés oxidativo.
- Para determinar si ATM puede ser activado independientemente de las rupturas de doble cadena de ADN y el complejo MRN.
Principales métodos:
- Análisis bioquímicos para detectar la activación y la dimerización de ATM.
- Mutagénesis dirigida al sitio de residuos críticos de cisteína en ATM.
- Pruebas celulares para evaluar la activación de ATM en respuesta a los agentes oxidantes.
Principales resultados:
- La oxidación induce directamente la activación de ATM, formando un dímero de enlaces cruzados con disulfuro, independiente de los DSB de ADN y del complejo MRN.
- La mutación de un residuo específico de cisteína abrogó la activación de ATM a través de la vía de oxidación.
- Esta vía explica la activación del ATM observada bajo condiciones de estrés oxidativo.
Conclusiones:
- El ATM funciona como un sensor directo de las especies reactivas de oxígeno (ROS).
- La modificación oxidativa representa una vía nueva y directa para la activación de ATM.
- Este hallazgo amplía la comprensión del papel del ATM en la respuesta al estrés celular.
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