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La activación del potenciador ligando-dependiente regulada por la actividad de la topoisomerasa-I
Janusz Puc1, Piotr Kozbial1, Wenbo Li1
1Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0648, USA.
Cell
|January 27, 2015
Resumen
Los investigadores descubrieron que el nicking de ADN por la ADN topoisomerasa I (TOP1) es esencial para activar potenciadores y sintetizar ARN potenciadores (eARN). Este proceso, desencadenado por la dihidrotestosterona (DHT) y el receptor de andrógenos (AR), implica el reclutamiento de la maquinaria de reparación del ADN.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- La epigenética es la epigenética.
- Biología del cáncer Biología del cáncer.
Sus antecedentes:
- Los potenciadores son elementos reguladores del ADN que controlan la expresión génica.
- Los potenciadores funcionan como unidades de transcripción, produciendo ARN potenciadores (eARN).
- Los mecanismos de activación del potenciador dependiente de ligandos aún no se comprenden completamente.
Objetivo del estudio:
- Para dilucidar el mecanismo molecular de la activación del potenciador ligando dependiente.
- Investigar el papel de la topoisomerasa I del ADN (TOP1) en la síntesis de eRNA y la función del potenciador.
- Modelar este mecanismo utilizando la unión al receptor de andrógenos (AR) inducida por dihidrotestosterona (DHT) en las células de cáncer de próstata.
Principales métodos:
- Utilizó dihidrotestosterona (DHT) para inducir la unión del receptor de andrógenos (AR) a los potenciadores en las células de cáncer de próstata.
- Monitoreó el reclutamiento de la topoisomerasa I del ADN (TOP1), ATR y el complejo MRN a potenciadores regulados por AR.
- Se evaluó el impacto de la actividad de nicking de ADN de TOP1 en la síntesis de eRNA y la activación del potenciador.
Principales resultados:
- Se ha demostrado el rápido reclutamiento de TOP1 a potenciadores regulados por AR a los pocos minutos de la inducción de DHT.
- Se estableció que la actividad de nicking de ADN de TOP1 es un requisito previo para una síntesis robusta de eRNA y la activación del potenciador.
- Se observó un reclutamiento coordinado de ATR, complejo MRN y maquinaria de reparación de daños en el ADN después del reclutamiento de TOP1.
Conclusiones:
- Reveló un nuevo mecanismo de activación del potenciador dependiente de ligandos que involucra el nicking de ADN mediado por TOP1 para aliviar el estrés de torsión durante la síntesis de eRNA.
- Se destacó un vínculo directo entre la síntesis de eRNA y la actividad de TOP1 en la regulación de la transcripción dependiente de potenciadores AR.
- Sugiere que esta estrategia de nicking impacta cuantitativamente la expresión de eRNA y los programas de transcripción en los cánceres impulsados por AR.
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