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Mol Cell Biol. 2009 Oct;29(19):5203-13. doi: 10.1128/MCB.00402-09. Epub 2009 Aug 3.

The S-phase checkpoint is required to respond to R-loops accumulated in THO mutants.

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


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 hpr1Delta 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.

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