Expression Floor Brush 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 e-port power connecting wire proteins, including MBF-regulated Ctp1CtIP, 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 Cdc18Cdc6 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.