Referencia

Genes Dev. 2014 Apr 1;28(7):735-48.

Autores

Emilia Herrera-Moyano, Xénia Mergui, María L. García-Rubio, Sonia Barroso y Andrés Aguilera.

Resumen

FACT (facilitates chromatin transcription) is a chromatin-reorganizing complex that swaps nucleosomes around the RNA polymerase during transcription elongation and has a role in replication that is not fully understood yet. Here we show that recombination factors are required for the survival of yeast FACT mutants, consistent with an accumulation of DNA breaks that we detected by Rad52 foci and transcription-dependent hyperrecombination. Breaks also accumulate in FACT-depleted human cells, as shown by γH2AX foci and single-cell electrophoresis. Furthermore, FACT-deficient yeast and human cells show replication impairment, which in yeast we demonstrate by ChIP–chip (chromatin immunoprecipitation [ChIP] coupled with microarray analysis) of Rrm3 to occur genome-wide but preferentially at highly transcribed regions. Strikingly, in yeast FACT mutants, high levels of Rad52 foci are suppressed by RNH1 overexpression; R loops accumulate at high levels, and replication becomes normal when global RNA synthesis is inhibited in FACT-depleted human cells. The results demonstrate a key function of FACT in the resolution of R-loop-mediated transcription–replication conflicts, likely associated with a specific chromatin organization.

Descripción

Este trabajo describe una nueva función del complejo reorganizador de la cromatina FACT, identificado originalmente por su papel en transcripción. Demuestra en la levadura Saccharomyces cerevisiae y en células humanas que la actividad reorganizadora de cromatina de FACT es fundamental para que una horquilla de replicación atraviese una región que se está transcribiendo y en la que se acumulan híbridos de DNA-RNA. El resultado está de acuerdo con que dichos híbridos alteran la estructura de la cromatina. De esta forma, FACT reorganiza la cromatina en las zonas de colisión entre la replicación y la transcripción previniendo roturas cromosómicas responsables de la inestabilidad genómica.

grupo

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de “Inestabilidad Genómica” dirigido por Andrés Aguilera en CABIMER investiga los factores y mecanismos implicados en la estabilidad del genoma en S. cerevisiae, C. elegans y células humanas. Su investigación se centra en determinar las causas y consecuencias del estrés replicativo y los defectos en reparación del DNA, especialmente en aquellos casos asociados a la transcripción y la formación de híbridos RNA-DNA, que constituyen un desafío para la replicación y la integridad del genoma con consecuencias importantes en envejecimiento y cáncer.

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