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CtIP-BRCA1 modula la elección de la vía de reparación de la ruptura de doble cadena de ADN a lo largo del ciclo
1Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
Nature
|April 10, 2009
Resumen
La proteína CtIP actúa como un interruptor del ciclo celular, dirigiendo la reparación de la ruptura de doble hebra del ADN. Su fosforilación en la serina 327 promueve la recombinación homóloga sin errores en S/G2, mientras que MMEJ domina en G1.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
- Genética La genética.
Sus antecedentes:
- Las rupturas de doble cadena de ADN (DSB) se reparan a través de vías distintas a lo largo del ciclo celular.
- La unión final no homóloga (NHEJ) y la unión final mediada por microhomología (MMEJ) son vías propensas a errores que prevalecen en G1.
- La recombinación homóloga (RH) es una vía libre de errores favorecida en las fases S/G2.
Objetivo del estudio:
- Para aclarar el mecanismo que controla la elección entre diferentes vías de reparación del ADN para DSBs.
- Identificar el papel de CtIP (RBBP8) en dirigir la selección de la vía de reparación de DSB durante el ciclo celular.
Principales métodos:
- Utilizó la línea aviar de células B DT40.
- Investigó la función de CtIP en las vías de reparación de DSB.
- Se analizó el impacto de la fosforilación de la serina 327 de CtIP y el reclutamiento de BRCA1 en la fidelidad de la reparación.
Principales resultados:
- El CtIP es esencial tanto para el MMEJ en G1 como para HR en S/G2.
- La función HR del CtIP, pero no la MMEJ, depende de la fosforilación de la serina 327 y el reclutamiento de BRCA1.
- El CtIP mutante que carece de fosforilación de la serina 327 deteriora la HR y reduce el ADN monocatenario después del daño, mientras que el MMEJ no se ve afectado.
Conclusiones:
- La fosforilación de CtIP en la serina 327 actúa como un interruptor molecular dependiente del ciclo celular.
- Este interruptor, junto con el reclutamiento de BRCA1, cambia la reparación de DSB de la unión final propensa a errores a la recombinación homóloga libre de errores.
- CtIP juega un papel crítico en el mantenimiento de la integridad genómica mediante la regulación de la elección de la vía de reparación DSB.
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