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Dot1p modula el silenciamiento en la levadura mediante la metilación del núcleo del nucleosoma
Fred van Leeuwen1, Philip R Gafken, Daniel E Gottschling
1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Cell
|June 28, 2002
Resumen
La proteína Dot1 metila la histona H3 y la lisina 79, un marcador epigenético clave. Esta metilación es crucial para mantener el silenciamiento genético en la cromatina, impactando el silenciamiento telomérico en la levadura.
Área de la Ciencia:
- La epigenética y la biología molecular.
- Biología de la cromatina Biología de la cromatina
- Genética de la levadura Genética de la levadura
Sus antecedentes:
- El silenciamiento telomérico en Saccharomyces cerevisiae (levadura) es un fenómeno bien estudiado.
- El gen DOT1 fue identificado inicialmente por su papel en este proceso de silenciamiento.
- Las modificaciones de la histona son reguladores críticos de la expresión génica y la estructura de la cromatina.
Objetivo del estudio:
- Para dilucidar la función molecular del producto del gen DOT1, Dot1p.
- Para identificar la modificación específica de la histona catalizada por Dot1p.
- Para entender el papel de esta modificación en el silenciamiento telomérico y la regulación de la cromatina.
Principales métodos:
- Pruebas bioquímicas para determinar la actividad enzimática de Dot1p.
- Inmunoprecipitación de cromatina (ChIP) para evaluar la localización de las proteínas.
- Análisis del silenciamiento de genes y la distribución de proteínas en cepas de levadura de tipo silvestre y dot1delta.
Principales resultados:
- Se encontró que Dot1p metila específicamente la histona H3 en la lisina 79 (metilación de H3K79).
- Esta metilación ocurre en el contexto de la cromatina ensamblada.
- Dot1p es la enzima principal responsable de la metilación de H3K79 in vivo, afectando aproximadamente al 90% de la histona H3.
- La pérdida de la función Dot1p (dot1delta) compromete el silenciamiento y altera la distribución de las proteínas silenciadoras.
Conclusiones:
- La metilación de la histona H3 lisina 79 por Dot1p es esencial para el silenciamiento telomérico adecuado.
- La metilación de H3K79 probablemente restringe el silenciamiento a loci específicos al evitar la unión de proteínas silenciadoras (como las proteínas Sir) a otras regiones genómicas.
- La naturaleza conservada de Dot1p e histona H3 sugiere que mecanismos de regulación epigenéticos similares operan en otros eucariotas.
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