Key Points
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The G1–S transcriptional programme is robustly activated by positive feedback mechanisms, creating an 'all-or-none' switch that leads to cell cycle commitment. Inactivation of G1–S transcription in both yeast and humans involves negative feedback loops.
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The wave of G1–S transcripts consists of subgroups based on their function, timing and mechanism of regulation.
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G1–S transcription is mechanistically linked to the DNA replication checkpoint by shared transcription factors in both yeast and humans in order to promote genomic stability during replication stress.
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Systems level properties associated with G1 control, such as the commitment point to cell division, the temporal pattern of G1–S transcription and its response to genotoxic stress, are likely to be conserved across eukaryotes despite frequent lack of protein sequence homology within the regulatory network.
Abstract
The accurate transition from G1 phase of the cell cycle to S phase is crucial for the control of eukaryotic cell proliferation, and its misregulation promotes oncogenesis. During G1 phase, growth-dependent cyclin-dependent kinase (CDK) activity promotes DNA replication and initiates G1-to-S phase transition. CDK activation initiates a positive feedback loop that further increases CDK activity, and this commits the cell to division by inducing genome-wide transcriptional changes. G1–S transcripts encode proteins that regulate downstream cell cycle events. Recent work is beginning to reveal the complex molecular mechanisms that control the temporal order of transcriptional activation and inactivation, determine distinct functional subgroups of genes and link cell cycle-dependent transcription to DNA replication stress in yeast and mammals.
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Acknowledgements
C.B and R.A.M de Bruin were funded by the Medical Research Council (MRC). J.M.S. was funded by the National Institutes of Health (NIH) (GM092925) and the Burroughs Wellcome Fund. The authors thank A. Johnson and C. Schwarz for careful reading of the manuscript. They apologize to colleagues whose work could only be cited indirectly.
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Glossary
- Ubiquitin ligase
-
An enzyme that recognizes Lys residues on a target protein and causes the attachment of ubiquitin to these residues.
- RB
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A protein that binds activator E2F proteins to inhibit transcription outside of G1–S in animals. RB is an oncoprotein that is dysfunctional in several major cancers.
- Pocket proteins
-
Family of proteins, including RB, p107 and p130, that associates with members of the E2F transcription factor family to inhibit transcription. The pocket domain is essential for tumour suppressing activity.
- Whi5
-
An inhibitor of SBF (SCB-binding factor)-dependent transcription during early G1 in yeast.
- Regulon
-
A collection of genes under the control of the same regulatory protein.
- Nrm1 and Yox1
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Nrm1 in budding yeast and Nrm1 and Yox1 in fission yeast bind MBF (MCB-binding factor) to inhibit transcription once cells transit into S phase.
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Bertoli, C., Skotheim, J. & de Bruin, R. Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol 14, 518–528 (2013). https://doi.org/10.1038/nrm3629
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DOI: https://doi.org/10.1038/nrm3629
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