Referencia

EMBO J. 2013 May 2;32(9):1307-21. doi: 10.1038/emboj.2013.73. Epub 2013 Apr 5.

Autores

Román González-Prieto, Ana M Muñoz-Cabello, María J Cabello-Lobato and Félix Prado

Resumen

Homologous recombination (HR) is essential for genome integrity. Recombination proteins participate in tolerating DNA lesions that interfere with DNA replication, but can also generate toxic recombination intermediates and genetic instability when they are not properly regulated. Here, we have studied the role of the recombination proteins Rad51 and Rad52 at replication forks and replicative DNA lesions. We show that Rad52 loads Rad51 onto unperturbed replication forks, where they facilitate replication of alkylated DNA by non-repair functions. The recruitment of Rad52 and Rad51 to chromatin during DNA replication is a prerequisite for the repair of the non-DSB DNA lesions, presumably single-stranded DNA gaps, which are generated during the replication of alkylated DNA. We also show that the repair of these lesions requires CDK1 and is not coupled to the fork but rather restricted to G2/M by the replicative checkpoint. We propose a new scenario for HR where Rad52 and Rad51 are recruited to the fork to promote DNA damage tolerance by distinct and cell cycle-regulated replicative and repair functions.

Descripción

La recombinación homóloga (HR) facilita la reparación de daños en el ADN mediante mecanismos que utilizan una secuencia de ADN no dañada como molde. En este trabajo demostramos que las proteínas de HR Rad52 y Rad51 viajan con las horquillas de replicación. Esta unión es esencial para la tolerancia a daños que interfieren con el avance de las horquillas, actividad que realizan mediante funciones replicativas y reparacionales separadas espacial y temporalmente, y reguladas por las quinasas tanto de checkpoint como dependientes de ciclo. Esta regulación es esencial para el mantenimiento de la estabilidad genética, probablemente porque evita que la reparación del daño interfiera con la replicación y genere reordenamientos genómicos.

grupo

REFERENCIA DEL GRUPO INVESTIGADOR

El mantenimiento de la integridad genómica y la correcta progresión a lo largo del ciclo celular son esenciales para prevenir la inestabilidad genética asociada al cáncer y a numerosas enfermedades genéticas. El objetivo del grupo del Dr. Prado es entender los mecanismos moleculares implicados en la generación y posterior reparación/tolerancia de daños en el ADN, su coordinación con los mecanismos de control de ciclo celular, y el papel que juega la cromatina en estos procesos. En particular, sus trabajos más recientes se han centrado en el papel del ensamblaje de la cromatina en la estabilidad de las horquillas de replicación y su efecto sobre la integridad genómica y la progresión a lo largo del ciclo, y en el papel de las proteínas de recombinación homóloga en los mecanismos de tolerancia a daños replicativos.

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