Reference

nature medicineProc Natl Acad Sci U S A. 2015 May 5;112(18):5779-84. doi: 10.1073/pnas.1501769112. Epub 2015 Apr 20

Authors

Ruth Stuckey*, Néstor García-Rodríguez*, Andrés Aguilera, and Ralf Erik Wellinger. *both authors contributed equally to this work

Abstract

DNA replication initiates at defined replication origins along eukaryotic chromosomes, ensuring complete genome duplication within a single S-phase. A key feature of replication origins is their ability to control the onset of DNA synthesis mediated by DNA polymerase-α and its intrinsic RNA primase activity. Here, we describe a novel origin-independent replication process that is mediated by transcription. RNA polymerase I transcription constraints lead to persistent RNA:DNA hybrids (R-loops) that prime replication in the ribosomal DNA locus. Our results suggest that eukaryotic genomes have developed tools to prevent R-loop-mediated replication events that potentially contribute to copy number variation, particularly relevant to carcinogenesis.

Description

En el presente estudio se ha identificado un modo de síntesis de ADN ribosómico que no requiere los orígenes canónicos de replicación en levadura. Este tipo de replicación depende de la acumulación de estrés torsional y de la transcripción de ARN. Como consecuencia, la replicación iniciada por transcripción puede tener un papel en la evolución de los genomas y contribuir a enfermedades humanas así como a la formación de tumores.

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REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de Plasticidad Mitocondrial y Replicación del Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER) dirigido por el Dr. Ralf Wellinger estudia la replicación en células eucariotas dañadas por luz UV o expuestas a estrés oxidativo o torsional. En concreto, para estudiar la relación entre el estrés torsional y la inestabilidad genética, los investigadores Ruth Stuckey y Néstor García Rodríguez se han centrado en el estudio de la topoisomerasa I. Este enzima representa una diana importante en la quimioterapia de tumores abriendo nuevas posibilidades en el desarrollo de fármacos más efectivos y con menores efectos secundarios.

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