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Los dominios de unión a la ubiquitina en las polimerasas de la familia Y regulan la síntesis de la translesión
Marzena Bienko1, Catherine M Green, Nicola Crosetto
1Institute for Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Science (New York, N.Y.)
|December 17, 2005
Resumen
Los investigadores descubrieron dominios de unión a la ubiquitina en las polimerasas de la familia Y, esenciales para la síntesis de traslación (TLS) a través de lesiones en el ADN. Estos dominios facilitan el reclutamiento de la polimerasa y la reparación del ADN, cruciales para la respuesta celular al daño del ADN.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Genética La genética.
- Biología celular Biología celular.
Sus antecedentes:
- La síntesis de traslación (TLS) es una vía crítica de reparación del ADN en las células de mamíferos, que permite la replicación a través de lesiones del ADN.
- Se sabe que la ubiquitinación del antígeno nuclear de la célula proliferante (PCNA) dirige la maquinaria de replicación a la vía TLS en caso de daño al ADN.
- El mecanismo preciso por el cual las células reconocen e interpretan la ubiquitinación de PCNA en TLS sigue siendo incompletamente entendido.
Objetivo del estudio:
- Identificar y caracterizar nuevos dominios de proteínas involucrados en el reconocimiento de PCNA ubiquitinado durante la síntesis de la translesión.
- Para aclarar la importancia funcional de estos dominios en el reclutamiento y la actividad de las polimerasas de ADN de la familia Y.
Principales métodos:
- Identificación de los dominios de unión a la ubiquitina conservados (UBM y UBZ) en las polimerasas TLS de la familia Y.
- Ensayos bioquímicos para evaluar la unión de las polimerasas a la ubiquitina y al PCNA monoubiquitinado.
- Estudios de localización celular para observar la acumulación de polimerasa en las fábricas de replicación.
- Ensayos de complementación funcional en los fibroblastos de la variante de xeroderma pigmentosum (XP-V).
Principales resultados:
- Se identificaron dos dominios de unión a la ubiquitina evolutivamente conservados, UBM y UBZ, en las polimerasas TLS de la familia Y.
- Estos dominios median la unión de las polimerasas eta (poleta) y iota (poliota) a la ubiquitina.
- Los dominios identificados son cruciales para la acumulación de estas polimerasas en las fábricas de replicación y su interacción con el PCNA monoubiquitinado.
- El dominio UBZ de poleta es esencial para restaurar la respuesta normal a la irradiación ultravioleta (UV) en las células XP-V.
Conclusiones:
- Los dominios de unión a la ubiquitina (UBM y UBZ) en las polimerasas de la familia Y son reguladores clave de la vía de síntesis de la traslación.
- Estos dominios facilitan el reclutamiento de las polimerasas TLS a las lesiones del ADN al interactuar con el PCNA monoubiquitinado.
- Los hallazgos proporcionan información crítica sobre los mecanismos moleculares que rigen la tolerancia y la reparación del daño en el ADN.
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