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In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones

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Published on: July 25, 2019

Mecanismos de lectura y escritura de la ubiquitinación H2A por el complejo represivo Polycomb 1

Victoria Godínez López¹, Marco Igor Valencia-Sánchez¹, Stephen Abini-Agbomson¹

¹Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.

|November 13, 2024

Resumen

El complejo represivo no canónico Polycomb 1 (ncPRC1^RYBP) restaura la monoubiquitinación de la histona H2AK119 (H2AK119Ub) a través de un nuevo mecanismo de lectura y escritura, asegurando la memoria celular durante la embriogénesis.

Área de la Ciencia:

La epigenética
Biología molecular
Biología estructural

Sus antecedentes:

La herencia epigenética se basa en el mantenimiento de dominios de cromatina silenciosos a través de modificaciones histónicas.
La histona H2A lisina 119 monoubiquitinación (H2AK119Ub) es crucial para el silenciamiento, pero se diluye durante la replicación del ADN.
El complejo represivo Polycomb 1 (PRC1) es responsable del restablecimiento de H2AK119Ub, pero su mecanismo no está claro.

Objetivo del estudio:

Para aclarar el mecanismo por el cual el PRC1 no canónico que contiene RYBP (ncPRC1^RYBP) restaura H2AK119Ub.
Caracterizar los aspectos estructurales y funcionales del mecanismo de lectura y escritura ncPRC1.
Comprender el papel de ncPRC1 en el mantenimiento de la memoria celular y la regulación epigenética.

Principales métodos:

Microscopía cryoelectrónica (cryo-EM) para determinar la estructura del ncPRC1^RYBP.
Pruebas funcionales para evaluar la actividad de la ligasa E3 de ncPRC1^RYBP.
Enfoques bioquímicos para el estudio de la unión del nucleosoma y la ubiquitinación.

Principales resultados:

ncPRC1^RYBP se une asimétricamente a los nucleosomas H2AK119Ub, con el dominio de dedo de zinc de RYBP reconociendo el H2AK119Ub existente.
Esta unión asimétrica posiciona los dominios RING para la restauración intra e internucleosómica de H2AK119Ub.
Se identificó un mecanismo de retroalimentación positiva para el restablecimiento de H2AK119Ub.

Conclusiones:

ncPRC1^RYBP emplea un mecanismo único de lectura y escritura para restaurar eficientemente H2AK119Ub.
Este mecanismo es vital para mantener los dominios de cromatina silenciosos y la memoria celular.
Los hallazgos proporcionan información crítica sobre la regulación epigenética y la función de los complejos Polycomb.

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