Un equipo internacional de investigadores con participación del Consejo Superior de Investigaciones Científicas (CSIC) ha descubierto una nueva vía por la que las células sanas y tumorales responden a la quimioterapia.
Una nueva proteína, denominada ZATT, consigue reestructurar y modificar las roturas del ADN provocadas por la quimioterapia, facilitando su reparación y, por tanto, el funcionamiento y la supervivencia celular. El estudio, publicado en la revista Science, puede contribuir a desarrollar futuras herramientas tanto de pronóstico como de intervención terapéutica.
“A la espera de nuevos tratamientos, la quimioterapia continúa siendo una herramienta fundamental en la lucha contra el cáncer”, explica Felipe Cortés, co-líder del estudio e investigador del CSIC en el Centro Andaluz de Biología Molecular y Medicina Regenerativa (centro mixto del CSIC, la Fundación Progreso y Salud, la Junta de Andalucía, la Universidad de Sevilla y la Universidad Pablo de Olavide). “Un grupo importante de agentes antitumorales basa su eficacia en la inducción de roturas en el ADN que afectan de manera preferente al crecimiento y la supervivencia de las células cancerosas, y atenúan así la progresión del tumor”, añade.
"Las roturas en el ADN producidas por estos agentes se caracterizan por contener unos bloqueos proteicos que necesitan eliminarse de los extremos de la rotura para permitir que el daño se repare y se reconstituya así la integridad del material genético. Es decir, las roturas tienen que ‘limpiarse’ antes de poder volver a ‘pegarse’, lo que es esencial para garantizar el funcionamiento y la supervivencia celular”, detalla Cortés. “Por lo tanto, los mecanismos que limpian estas roturas, tanto en el tumor como en el tejido sano, determinan en gran medida la respuesta celular a estos agentes y, en última instancia, la eficacia del tratamiento y sus efectos secundarios”.
Hasta la fecha se pensaba que para la limpieza de los extremos de las roturas era necesario un paso en el que el bloqueo proteico se degrada. “Esta degradación deja pequeños residuos que se eliminan posteriormente de forma específica mediante la acción de una enzima altamente especializada llamada TDP2, y que descubrimos en 2009”, indica el investigador.
En este trabajo, los investigadores demuestran que las roturas se pueden limpiar de forma directa, sin necesidad de degradación, mediante la acción de ZATT, una nueva proteína que han identificado y que tiene la capacidad de reestructurar y modificar los extremos para facilitar la actividad de TDP2.
“En definitiva, hemos descubierto una nueva vía por la que las células pueden responder a la quimioterapia”, señala Cortés. “Estos conocimientos deben constituir la base de futuras herramientas tanto de pronóstico como de intervención terapéutica. Es decir, por un lado, la funcionalidad de esta ruta de reparación (por ejemplo midiendo los niveles de TDP2 y ZATT) puede emplearse para predecir la respuesta del tumor a la quimioterapia, lo que puede ayudar en la estratificación de pacientes y el diseño de tratamientos personalizados. Por otro lado, nuevas moléculas que inhiban la ruta TDP2-ZATT podrían emplearse para aumentar la sensibilidad de tumores a estos tratamientos y evitar el desarrollo de posibles resistencias”.
Artículo de referencia: Matthew J. Schellenberg, Jenna Ariel Lieberman, Andrés Herrero-Ruiz, Logan R. Butler, Jason G. Williams, Ana M. Muñoz-Cabello, Geoffrey A. Mueller, Robert E. London, Felipe Cortés-Ledesma, and R. Scott Williams. ZATT (ZNF451)-Mediated Resolution of Topoisomerase 2 DNA-Protein Crosslinks. Science.
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