Bertoli, C., Klier, S., McGowan, C., Wittenberg, C., De Bruin, R. A. M. (2013). Chk1 inhibits E2F6 repressor function in response to replication stress to maintain cell-cycle transcription. Current Biology
Cancer is a group of diseases in which cells continue to multiply in an unregulated manner. The main regulation of initiation of a new cell division cycle is imposed during a specific phase of the cell cycle called G1. Proteins that control exit from G1-phase, including those involved in regulating G1-S transcription, are often found mutated in human tumour cells, suggesting that inactivation of this pathway may be necessary for tumour development.
Once a cell commits to a new cell division cycle the DNA structure checkpoints can restrict cell-cycle progression in response to the detection of abnormalities in the genetic material in order to repair the detected damage. When these checkpoints fail, cells are at risk of increased genetic abnormalities, phenomena that are associated with tumour development. Part of the checkpoint control includes regulation of the cell cycle transcriptional program. However, it was not understood how checkpoints act on the cell cycle transcription program, nor has the functional significance of this control been rigorously tested in any experimental system.
We recently identified the novel transcriptional repressor Nrm1 as a key regulator in turning off G1-S transcription during exit from the G1 phase of the cell cycle in both budding Saccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe . We established that Nrm1, which performs an analogous function to the mammalian pocket proteins, is a target of the DNA replication checkpoint pathway. This suggests that it is at the nexus between the cell-cycle transcriptional program and the DNA replication checkpoint.
This presents a unique opportunity to achieve an unprecedented level of understanding about the relationship between cell-cycle regulated transcription and control of genome integrity. The degree of conservation from yeast to human of both the G1-S transcription network and the DNA replication checkpoint response suggest that regulation of G1-S transcription by the DNA replication checkpoint may also be conserved in mammals. Our latest work does indicate that regulation of G1-S transcription by the DNA replication checkpoint is conserved in human cells. The opportunity to study this regulation in both yeasts promises to reveal conserved aspects of its function that will guide our future research into human biology and disease. In that context, our main aim is to investigate the spectrum of activities, resulting from regulating G1-S genes by the DNA structure checkpoints that can contribute to recovery from genotoxic stress in eukaryotes.