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RTEL1 mantiene la estabilidad genómica suprimiendo la recombinación homóloga
Louise J Barber1, Jillian L Youds, Jordan D Ward
1DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms EN6 3LD, UK.
Cell
|October 30, 2008
Resumen
Los científicos identificaron RTEL-1 en gusanos y RTEL1 en vertebrados como clave para la reparación del ADN y la estabilidad del genoma, funcionando de manera similar a la levadura Srs2.2. La pérdida de la función de RTEL1 conduce a la sensibilidad al daño del ADN y puede conducir al cáncer.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Genética La genética.
- Investigación del cáncer Investigación del cáncer.
Sus antecedentes:
- La recombinación homóloga (RH) es crucial para la reparación del ADN y la integridad del genoma.
- La HR desregulada puede conducir a anomalías cromosómicas y cáncer.
- La helicasa Srs2 de la levadura previene la HR inapropiada, pero su equivalente eucariótico más alto era desconocido.
Objetivo del estudio:
- Para identificar el análogo funcional de la levadura Srs2 en los eucariotas superiores.
- Para investigar el papel de este análogo en la estabilidad del genoma y la supresión de tumores.
Principales métodos:
- Identificó C. elegans RTEL-1 y su contraparte vertebrada RTEL1.
- Fenotipos analizados de gusanos mutantes rtel-1 y células humanas empobrecidas por RTEL1.
- Se realizaron ensayos in vitro con RTEL1 humano purificado para estudiar su mecanismo.
Principales resultados:
- C. elegans RTEL-1 y los vertebrados RTEL1 funcionan como análogos de Srs2.
- Las células mutantes / agotadas exhibieron fenotipos similares a los mutantes de la levadura srs2 (letalidad, hiperrecombinación, sensibilidad al daño del ADN).
- El RTEL1 humano desmonta los intermediarios de recombinación del bucle D de una manera dependiente del ATP.
Conclusiones:
- RTEL1 es esencial para la estabilidad del genoma y la prevención de tumores en eucariotas superiores.
- La pérdida del control de la HR debido a la desregulación de RTEL1 puede impulsar el desarrollo del cáncer.
- RTEL1 representa un objetivo crítico para comprender y potencialmente tratar el cáncer.
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