Reference

PNAS 2017 Sep 25. pii: 201707845. doi: 10.1073/pnas.1707845114 PNASnov

Authors

Francisco García-Benítez, Hélène Gaillard y Andrés Aguilera

Abstract

During transcription, the mRNA may hybridize with DNA, forming an R loop, which can be physiological or pathological, constituting in this case a source of genomic instability. To understand the mechanism by which eukaryotic cells prevent harmful R loops, we used human activation-induced cytidine deaminase (AID) to identify genes preventing R loops. A screening of 400 Saccharomyces cerevisiae selected strains deleted in nuclear genes revealed that cells lacking the Mlp1/2 nuclear basket proteins show AID-dependent genomic instability and replication defects that were suppressed by RNase H1 overexpression. Importantly, DNA-RNA hybrids accumulated at transcribed genes in mlp1/2 mutants, indicating that Mlp1/2 prevents R loops. Consistent with the Mlp1/2 role in gene gating to nuclear pores, artificial tethering to the nuclear periphery of a transcribed locus suppressed R loops in mlp1∆ cells. The same occurred in THO-deficient hpr1∆ cells. We conclude that proximity of transcribed chromatin to the nuclear pore helps restrain pathological R loops.

Description

La proximidad y anclaje de los genes a los poros nucleares cuando se transcriben se conoce desde hace más de una década. La misma facilita que el ARN naciente se exporte fuera del núcleo. Hemos descubierto que el anclaje del ADN al poro nuclear durante la transcripción evita la formación de híbridos de ADN-ARN que son una fuente natural de roturas del ADN e inestabilidad genómica. El trabajo revela que la dinámica espacial del ADN en el núcleo es determinante en el origen de la inestabilidad genómica asociada a ARN.

 

 

grupo REC

 

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 trata de entender los eventos de inestabilidad genómica asociados a la transcripción y a la replicación, el acoplamiento entre la transcripción con el transporte del ARN, y la importancia de los híbridos de ADN-ARN en la dinámica de los genomas.

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