title: Tolerance of deregulated G1/S transcription depends on critical G1/S regulon genes to prevent catastrophic genome instability.
abstract: 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.
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, WC1E 6BT London, UK.
authors.forename: Catia
authors.initials: C
authors.lastname: Caetano
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Limbo
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, WC1E 6BT London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Farmer
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, WC1E 6BT London, UK.
authors.forename: Steffi
authors.initials: S
authors.lastname: Klier
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Dovey
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: prussell@scripps.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Russell
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, WC1E 6BT London, UK; The UCL Cancer Institute, University College London, WC1E 6BT London, UK. Electronic address: r.debruin@ucl.ac.uk.
authors.forename: Robertus Antonius Maria
authors.initials: RA
authors.lastname: de Bruin
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D005800:Genes, Fungal; D042822:Genomic Instability; D018085:Regulon; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012568:Schizosaccharomyces / Q000235:genetics* / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C080328:Cig2 protein, S pombe; C525888:Ctp1 protein, S pombe; D019926:Cyclin B; D004268:DNA-Binding Proteins; C489911:DSC1 protein, S pombe; C531391:Nrm1 protein, S pombe; D012097:Repressor Proteins; D029702:Schizosaccharomyces pombe Proteins; D014157:Transcription Factors; C082462:cdc18 protein, S pombe