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ATM inicia la autodegradación de la E3 ubiquitina ligasa COP1 después del daño del ADN

David Dornan¹, Harumi Shimizu, Angie Mah

¹Department of Physiological Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Science (New York, N.Y.)

|August 26, 2006

Resumen

La proteína quinasa de la ataxia telangiectasia mutada (ATM) regula el eje COP1-p53 después del daño del ADN. La fosforilación ATM de COP1 en Ser{387} interrumpe la unión de COP1-p53, estabilizando p53 y sus funciones supresoras de tumores.

Área de la Ciencia:

Biología Molecular Biología Molecular
Biología celular Biología celular.
Genética La genética.

Sus antecedentes:

La proteína quinasa ataxia telangiectasia mutada (ATM) es crucial para la respuesta al daño del ADN y la integridad genómica.
La estabilidad de la proteína supresora de tumores p53 está regulada por las ligasas de ubiquitina E3, incluida la COP1, pero la vía regulada por el ATM no está clara.

Objetivo del estudio:

Para dilucidar la vía de transducción de la señal que regula el eje COP1-p53 después del daño del ADN.
Investigar el papel del ATM en la regulación de la COP1 y la p53.

Principales métodos:

Estudió el efecto del daño del ADN en las interacciones y localización de ATM, COP1 y p53.
Utilizó radiación ionizante para inducir daño en el ADN y analizó la fosforilación COP1 en Ser{387}.

Principales resultados:

ATM fosforila COP1 en Ser{387} en respuesta al daño del ADN, desencadenando la autodegradación COP1.
La radiación ionizante induce la translocación nuclear a citoplasmática dependiente del ATM de la COP1.
La fosforilación de la COP1 en el Ser ((387) por el ATM interrumpe el complejo COP1-p53, evitando la ubiquitinación y degradación de la p53.

Conclusiones:

La fosforilación dependiente de ATM de COP1 en Ser{387} es esencial para la estabilización de p53 y la actividad supresora de tumores después del daño del ADN.
Esta vía representa un nuevo mecanismo para regular la función de p53 en respuesta al estrés genómico.

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