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HPF1 completa el sitio activo de PARP para la ribosilación de ADP inducida por daño en el ADN
Marcin J Suskiewicz1, Florian Zobel1, Tom E H Ogden2
1Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Nature
|February 7, 2020
Resumen
HPF1 forma un sitio activo compuesto con PARP1/PARP2, crucial para la reparación del daño en el ADN a través de la ADP-ribosilación de la serina. Esta interacción es vital para la respuesta de la célula al daño del ADN y a los inhibidores clínicos de la PARP.
Área de la Ciencia:
- La bioquímica
- Biología molecular
- La genética
Sus antecedentes:
- La poli (ADP-ribosa) polimerasa 1 (PARP1) y la PARP2 son las respuestas clave al daño del ADN.
- Modifican las proteínas con señales de ADP-ribosa, ayudando a la descomposición de la cromatina y al reclutamiento de factores de reparación.
- Las modificaciones ligadas a la serina requieren HPF1, que altera la especificidad de PARP1/PARP2 para la respuesta al daño del ADN.
Objetivo del estudio:
- Esclarecer el papel estructural y funcional de HPF1 en la respuesta al daño del ADN mediado por PARP.
- Investigar la formación del sitio activo compuesto que involucra a las enzimas HPF1 y PARP.
- Comprender la regulación de las interacciones HPF1-PARP en respuesta al daño del ADN.
Principales métodos:
- Determinación de la coestructura de HPF1 con el dominio catalítico de PARP2.
- Espectroscopia de resonancia magnética nuclear (RMN).
- Ensayos bioquímicos para evaluar la actividad enzimática y las interacciones.
Principales resultados:
- Se reveló un sitio activo compuesto formado por residuos de HPF1 y PARP1/ PARP2.
- Este centro catalítico es esencial para el daño posterior a la adición de ADP-ribosa.
- Las redes alostéricas mejoran la interacción HPF1-PARP sobre el daño del ADN y la unión al NAD+, regulando la respuesta al daño del ADN.
Conclusiones:
- HPF1 es parte integral de la formación del sitio activo de PARP1 y PARP2 para la reparación de daños en el ADN.
- HPF1 actúa como un determinante crucial en la respuesta celular al daño del ADN.
- El papel de HPF1 en el sitio activo compuesto lo implica en la eficacia de los inhibidores clínicos de la PARP.
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