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Professor Mark Sansom, Head of Department
Single human cells reveal molecular mechanisms in cell cycle control
A new paper scrutinizing how mammalian cells control transition into the DNA replication phase of the cell cycle comes out in Cell Systems (1).
HeLa cells expressing p27 reporter (green) and PCNA (purple). Only cells in G1 express p27, which is rapidly degraded at the G1/S transition. PCNA is expressed throughout the cell cycle but is at a much lower level during G1 than during S and G2
(Click to enlarge)
The research is part of an ongoing collaboration between the labs of Bela Novak in the Department and Chris Bakal at the Institute of Cancer Research, London. Postdocs Alexis Barr at the ICR and Stefan Heldt in Oxford are responsible for much of the work. It provides a molecular explanation for how mammalian cells transition abruptly and irreversibly into the DNA replication phase. The work also provides insight into how other transitions in the cell cycle may be controlled.
Cells control DNA replication through an elaborate set of networks that are similar between yeast and mammalian cells. There are two distinct points that the cell must pass through to enter S-phase (DNA replication phase). The decision to proliferate takes place during the resting (G1) phase of the cell cycle - at 'Start' in yeast or the 'restriction point' in mammalian cells. The irreversible transition from G1- to S-phase and commitment to replication occurs shortly afterwards.
Cyclins are a family of proteins that are important for driving the cell into S-phase. By forming complexes with the Cyclin-dependent kinases (CDKs), Cyclins promote the activation of CDK activity. Different combinations of Cdk/Cyclins control different transitions within the cell cycle, and the G1/S transition is driven by the activity of Cdk2, in complex with either CyclinE or CyclinA. These Cyclins accumulate as their genes are turned on at the restriction point. However, full activation of Cdk2:Cyclin complexes first requires degradation of Cdk inhibitors (CKIs), such as the p27 protein, which keeps Cyclin:CDK complexes in an inactive state. On top of these controls are feedback loops that ensure that the G1/S transition is both abrupt and irreversible. The dynamic interactions between these different cell cycle components have been well described in yeast but are less well understood in more complex mammalian cells.