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Coordinated control of replication and transcription by a SAPK protects genomic integrity

Nature volume 493, pages 116–119 (2013)Cite this article

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Abstract

Upon environmental changes or extracellular signals, cells are subjected to marked changes in gene expression 1,2. Dealing with high levels of transcription during replication is critical to prevent collisions between the transcription and replication pathways and avoid recombination events3,4,5. In response to osmostress, hundreds of stress-responsive genes are rapidly induced by the stress-activated protein kinase (SAPK) Hog1 (ref. 6), even during S phase7. Here we show in Saccharomyces cerevisae that a single signalling molecule, Hog1, coordinates both replication and transcription upon osmostress. Hog1 interacts with and phosphorylates Mrc1, a component of the replication complex8,9,10,11. Phosphorylation occurs at different sites to those targeted by Mec1 upon DNA damage8,9. Mrc1 phosphorylation by Hog1 delays early and late origin firing by preventing Cdc45 loading, as well as slowing down replication-complex progression. Regulation of Mrc1 by Hog1 is completely independent of Mec1 and Rad53. Cells carrying a non-phosphorylatable allele of MRC1 (mrc13A ) do not delay replication upon stress and show a marked increase in transcription-associated recombination, genomic instability and Rad52 foci. In contrast, mrc13A induces Rad53 and survival in the presence of hydroxyurea or methyl methanesulphonate. Therefore, Hog1 and Mrc1 define a novel S-phase checkpoint independent of the DNA-damage checkpoint that permits eukaryotic cells to prevent conflicts between DNA replication and transcription, which would otherwise lead to genomic instability when both phenomena are temporally coincident.

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Figure 1: Mrc1 is a Hog1 target.
Figure 2: mrc1 3A bypasses the osmostress-induced S phase delay.
Figure 3: Hog1 delays replication by inhibiting fork progression and origin firing.
Figure 4: Hog1–Mrc1 checkpoint prevents genomic instability upon osmostress.

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Acknowledgements

We thank L. Subirana, S. Ovejas and A. Fernandez for technical support. This work was supported by grants from the Spanish Government (BIO2009-07762 and BFU2012-33503 to F.P., BFU2011-26722 to E.d.N., BFU2010-16372 to A.A., and Consolider Ingenio 2010 programme CSD2007-0015 to F.P. and A.A.) and FP7 UNICELLSYS grant (no. 201142) and the Fundación Marcelino Botín to F.P. F.P. and E.d.N. are recipients of an ICREA Acadèmia (Generalitat de Catalunya).

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Authors and Affiliations

  1. Cell Signaling Unit, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), Barcelona E-08003, Spain ,

    Alba Duch, Gilad Yaakov, Eulàlia de Nadal & Francesc Posas

  2. Centro Andaluz de Biología Molecular and Medicina Regenerativa CABIMER, Universidad de Sevilla, 41092 Sevilla, Spain ,

    Irene Felipe-Abrio, Sonia Barroso, María García-Rubio & Andrés Aguilera

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  1. Alba Duch
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Contributions

A.D. conducted most of the experiments. I.F.-A., S.B. and M.G.-R. worked on the analysis of replication. G.Y. initiated the studies. A.D., E.d.N., A.A., G.Y. and F.P. did the experimental designs. A.D., A.A., E.d.N. and F.P. wrote the paper.

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Correspondence to Francesc Posas.

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The authors declare no competing financial interests.

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Duch, A., Felipe-Abrio, I., Barroso, S. et al. Coordinated control of replication and transcription by a SAPK protects genomic integrity. Nature 493, 116–119 (2013). https://doi.org/10.1038/nature11675

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