Contributed by Marc W. Kirschner, June 7, 2013 (sent for review March 4, 2013)
The master cell-cycle processes governing DNA replication and mitosis in eukaryotic cells are regulated by cyclin/cyclin dependent kinase 1 and the anaphase-promoting complex, with checkpoint activity on these regulators. It is not these regulators but rather intermediaries that communicate to the processes. Here we show that the protein Geminin acts centrally in controlling DNA replication by ensuring that DNA is replicated during S phase and only once. This paper describes the Geminin “sub-master” regulatory circuit and the central role of Geminin in controlling events of the cell cycle.
Cdc10-dependent transcript 1 (Cdt1) is an essential DNA replication protein whose accumulation at the end of the cell cycle promotes the formation of pre-replicative complexes and replication in the next cell cycle. Geminin is thought to be involved in licensing replication by promoting the accumulation of Cdt1 in mitosis, because decreasing the Geminin levels prevents Cdt1 accumulation and impairs DNA replication. Geminin is known to inhibit Cdt1 function; its depletion during G2 leads to DNA rereplication and checkpoint activation. Here we show that, despite rapid Cdt1 protein turnover in G2 phase, Geminin promotes Cdt1 accumulation by increasing its RNA and protein levels in the unperturbed cell cycle. Therefore, Geminin is a master regulator of cell-cycle progression that ensures the timely onset of DNA replication and prevents its rereplication.
Author contributions: A.B. and M.W.K. designed research; A.B., R.Z., and J.K.M. performed research; A.B., R.Z., K.H., and M.W.K. contributed new reagents/analytic tools; A.B., R.Z., K.H., and M.W.K. analyzed data; and A.B. and M.W.K. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1310677110/-/DCSupplemental.
