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Molecular and Cellular Biology, October 2009, p. 5203-5213, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00402-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The S-Phase Checkpoint Is Required To Respond to R-Loops Accumulated in THO Mutants{triangledown} ,{dagger}

Belén Gómez-González, Irene Felipe-Abrio, and Andrés Aguilera*

Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla-CSIC, Av. Américo Vespucio s/n, 41092 Seville, Spain

Received 27 March 2009/ Returned for modification 5 May 2009/ Accepted 24 July 2009

Cotranscriptional R-loops are formed in yeast mutants of the THO complex, which functions at the interface between transcription and mRNA export. Despite the relevance of R-loops in transcription-associated recombination, the mechanisms by which they trigger recombination are still elusive. In order to understand how R-loops compromise genome stability, we have analyzed the genetic interaction of THO with 26 genes involved in replication, S-phase checkpoint, DNA repair, and chromatin remodeling. We found a synthetic growth defect in double null mutants of THO and S-phase checkpoint factors, such as the replication factor C- and PCNA-like complexes. Under replicative stress, R-loop-forming THO null mutants require functional S-phase checkpoint functions but not double-strand-break repair functions for survival. Furthermore, R-loop-forming hpr1{Delta} mutants display replication fork progression impairment at actively transcribed chromosomal regions and trigger Rad53 phosphorylation. We conclude that R-loop-mediated DNA damage activates the S-phase checkpoint, which is required for the cell survival of THO mutants under replicative stress. In light of these results, we propose a model in which R-loop-mediated recombination is explained by template switching.

* Corresponding author. Mailing address: Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla-CSIC, Av. Américo Vespucio s/n, 41092 Seville, Spain. Phone: 34 954 468 372. Fax: 34 954 461 664. E-mail: aguilo{at}us.es

{triangledown} Published ahead of print on 3 August 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, October 2009, p. 5203-5213, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00402-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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