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ATM fosforilados p95/nbs1 en una vía de punto de control de fase S
1Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Nature
|April 15, 2000
Resumen
La ataxia-telangiectasia (AT) y el síndrome de ruptura de Nijmegen (NBS) comparten sensibilidad a la radiación. La activación de la ATM quinasa en las células NBS y la fosforilación p95/nbs1 dependiente de ATM vinculan estas proteínas en una vía común de respuesta al daño del ADN.
Área de la Ciencia:
- Genética La genética.
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
Sus antecedentes:
- La ataxia-telangiectasia (AT) y el síndrome de ruptura de Nijmegen (NBS) son enfermedades raras con síntomas compartidos como la inestabilidad cromosómica y la sensibilidad a la radiación.
- Las mutaciones en los genes ATM (AT) y p95/nbs1 (NBS) subyacen a estas condiciones, afectando las vías de respuesta al daño del ADN.
Objetivo del estudio:
- Investigar la relación funcional entre ATM y p95/nbs1 debido a las similitudes observadas entre AT y NBS.
- Aclarar el papel de la fosforilación dependiente de ATM de p95/nbs1 en las respuestas celulares a la radiación ionizante.
Principales métodos:
- Evaluación de la activación de la ATM quinasa y las respuestas dependientes de ATM en las células NBS después de la radiación ionizante.
- Evaluación de la fosforilación in vitro e in vivo de p95/nbs1 en la serina 343.3.
- Utilizando un constructo p95/nbs1 mutado (no fosforilable) para examinar la función del punto de control de la fase S.
Principales resultados:
- La radiación ionizante activó la ATM quinasa e indujo respuestas dependientes de ATM en las células NBS, lo que sugiere que p95/nbs1 no es esencial para la señalización de ATM después de la irradiación.
- p95/nbs1 se somete a una fosforilación dependiente de ATM en serina 343 después de la radiación ionizante.
- Una construcción p95/nbs1 mutada que carece del sitio de fosforilación ATM interrumpió el punto de control de la fase S en las células normales y no pudo rescatar el defecto en las células NBS.
Conclusiones:
- ATM y p95/nbs1 están funcionalmente vinculados dentro de una vía de señalización común.
- La fosforilación dependiente de ATM de p95/nbs1 es crucial para la respuesta del punto de control de fase S a la radiación ionizante, lo que explica la superposición fenotípica entre AT y NBS.
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