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    Expression of a G1/S regulon of genes that are required for DNA replication is a ubiquitous mechanism for controlling cell proliferation; moreover, the pathological deregulated expression of E2F-regulated G1/S genes is found in every type of cancer. Cellular tolerance of deregulated G1/S transcription is surprising because this regulon includes many dosage-sensitive proteins. Here, we used the fission yeast Schizosaccharomyces pombe to investigate this issue. We report that deregulating the MBF G1/S regulon by eliminating the Nrm1 corepressor increases replication errors. Homology-directed repair proteins, including MBF-regulated Ctp1(CtIP), are essential to prevent catastrophic genome instability. Surprisingly, the normally inconsequential MBF-regulated S-phase cyclin Cig2 also becomes essential in the absence of Nrm1. This requirement was traced to cyclin-dependent kinase inhibition of the MBF-regulated Cdc18(Cdc6) replication origin-licensing factor. Collectively, these results establish that, although deregulation of G1/S transcription is well tolerated by cells, nonessential G1/S target genes become crucial for preventing catastrophic genome instability. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

    Citation

    Catia Caetano, Oliver Limbo, Sarah Farmer, Steffi Klier, Claire Dovey, Paul Russell, Robertus Antonius Maria de Bruin. Tolerance of deregulated G1/S transcription depends on critical G1/S regulon genes to prevent catastrophic genome instability. Cell reports. 2014 Dec 24;9(6):2279-89

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    PMID: 25533348

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