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Regulación independiente de la securina de la separasa por el shugoshin inducido por el punto de control-MAD2
Susanne Hellmuth1, Laura Gómez-H2, Alberto M Pendás2
1Chair of Genetics, University of Bayreuth, Bayreuth, Germany.
Nature
|April 24, 2020
Resumen
La shugosina 2 (SGO2) actúa como un nuevo inhibidor de la separasa, complementando la securina.
Área de la Ciencia:
- Biología celular
- Biología molecular
- La genética
Sus antecedentes:
- La separación de las cromatidas hermanas en las células eucariotas está regulada por el punto de control de ensamblaje del huso (SAC) y la proteasa separasa.
- La securina normalmente inhibe la separasa, y su degradación a través de APC/C (complejo promotor de la anafase) activa la separasa.
- La regulación de la separasa en ausencia de securina no ha quedado clara.
Objetivo del estudio:
- Investigar el papel de la shugosina humana 2 (SGO2) en la regulación de la actividad de la separasa en las células somáticas.
- Aclarar el mecanismo por el cual SGO2 inhibe la separasa y cómo se regula esta inhibición.
- Para comprender la interacción entre SGO2, la securina y el punto de control de ensamblaje del huso en la segregación cromosómica.
Principales métodos:
- Investigó la interacción entre SGO2 y MAD2 en el contexto del punto de control de ensamblaje del husillo.
- Se utilizaron células securin-knockout para estudiar la regulación de la separasa por SGO2.
- Se realizaron ensayos in vitro para analizar el mecanismo inhibidor de SGO2-MAD2 en la separasa y la regulación de este complejo.
Principales resultados:
- La shugosina humana 2 (SGO2) funciona como inhibidor de la separasa al unirse a la MAD2 activada por el SAC, formando un complejo SGO2-MAD2.
- El complejo SGO2-MAD2 secuestra efectivamente la separasa, reemplazando funcionalmente la securina en las células de nocaut de la securina.
- La pérdida tanto de securina como de SGO2 conduce a la escisión prematura de la cohesión y a la citotoxicidad, lo que indica sus funciones cooperativas.
- SGO2 inhibe la separasa bloqueando su sitio activo a través de una secuencia de pseudo-sustrato, similar a la securina.
- La separasa se libera de SGO2-MAD2 a través de la ubicuidad dependiente de APC/C y la acción de TRIP13 y el cometa p31.
Conclusiones:
- Se identificó una nueva función de SGO2 como inhibidor de la separasa en las células somáticas en división mitótica.
- Descubrió un mecanismo de regulación de la separación independiente de la securin supervisado por el punto de control de ensamblaje del husillo.
- El complejo SGO2-MAD2 proporciona una salvaguardia crucial para controlar la actividad de la separasa, especialmente cuando la securina está ausente.
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