Upf1, an RNA Helicase Required for Nonsense-Mediated mRNA Decay, Modulates the Transcriptional Response to Oxidative Stress in Fission Yeast

Abstract

In the fission yeast Schizosaccharomyces pombe, oxidative stress triggers the activation of the Spc1/Sty1 mitogen-activated protein kinase, which in turn phosphorylates the Atf1/Pcr1 heterodimeric transcription factor to effect global changes in the patterns of gene expression. This transcriptional response is also controlled by Csx1, an RNA-binding protein that directly associates with and stabilizes atf1⁺ mRNA. Here we report the surprising observation that this response also requires Upf1, a component of the nonsense-mediated mRNA decay (NMD) system. Accordingly, upf1Δ and csx1Δ strains are similarly sensitive to oxidative stress, and the effects of the mutations are not additive, suggesting that Upf1 and Csx1 work in the same pathway to stabilize atf1⁺ mRNA during oxidative stress. Consistent with these observations, whole-genome expression profiling studies have shown that Upf1 controls the expression of more than 100 genes that are transcriptionally induced in response to oxidative stress, the large majority of which are also controlled by Atf1 and Csx1. The unexpected connection between an NMD factor and the oxidative stress response in fission yeast may provide important new clues about the physiological function of NMD in other species.

We thank the Scripps Cell Cycle Group and members of the Russell laboratory for support and encouragement and Rosa M. Perez (Unidad de Genomica, UCM) for her technical help. Victoria Martin and Charly Chahwan provided useful suggestions.

The project was supported by grant number ES10337 from the National Institute of Environmental Health Sciences, NIH (P.R.), and Cancer Research UK (J.B.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH. M.A.R.-G. is a Ramon y Cajal investigator.