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El núcleo 1 de la proteína de unión al poli (A) suprime los sitios alternativos de escisión y poliadenilación

Mathias Jenal¹, Ran Elkon, Fabricio Loayza-Puch

¹Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

|April 17, 2012

Resumen

La proteína de unión al núcleo 1 (PABPN1) suprime la escisión alternativa y la poliadenilación (APA), un proceso regulador de genes clave. La pérdida de PABPN1 conduce al acortamiento de la región 3' no traducida e impacta en la regulación del microARN.

Área de la Ciencia:

Biología Molecular Biología Molecular
Regulación genética Reglamento genético.
Procesamiento de ARN Procesamiento de ARN

Sus antecedentes:

La escisión y poliadenilación alternativas (APA) es un mecanismo crítico para la regulación genética post-transcripcional.
Los factores específicos que controlan los eventos de APA siguen siendo en gran medida no identificados.
La desregulación de la APA está implicada en varias enfermedades humanas.

Objetivo del estudio:

Para identificar nuevos reguladores de APA utilizando una pantalla de RNAi de alto rendimiento.
Para aclarar los mecanismos moleculares por los cuales PABPN1 controla APA.
Para investigar el papel de PABPN1 en la patogénesis de la distrofia muscular oculofaríngea (OPMD).

Principales métodos:

Desarrollo de una pantalla de RNAi basada en reporteros para APA.
Perfilado APA de todo el genoma en células humanas.
Análisis de la transcripción y la estabilidad del ARN mensajero.
Ensayos de escisión in vitro. ensayos de escisión in vitro.
Expresión del mutante PABPN1 en cultivos celulares y en un modelo de ratón.

Principales resultados:

Identificación de PABPN1 como un nuevo regulador de la APA.
La pérdida de la función de PABPN1 conduce a un acortamiento generalizado de la región no traducida 3' debido al mayor uso de sitios de escisión proximales.
Esta desregulación de la APA perjudica la represión génica mediada por microARN.
El mutante PABPN1 (trePABPN1) encontrado en OPMD causa el uso del sitio de escisión proximal y la formación de agregados nucleares.

Conclusiones:

PABPN1 actúa como un supresor crucial de la escisión alternativa y la poliadenilación.
La función de PABPN1 en la regulación de la APA se ve comprometida en la OPMD, lo que contribuye a la patología de la enfermedad.
Comprender el papel de PABPN1 en la APA abre nuevas vías para las intervenciones terapéuticas en la OPMD y otras enfermedades que implican la desregulación de la APA.

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