Cell Biology
Ron Laskey
Professor of Animal Embryology
Email: ral19@cam.ac.uk
Tel.: +44 (0)1223 334106
We study the control of mammalian DNA replication and especially that of human cells. Using cultured cells we have developed cell free systems that initiate DNA replication in vitro to study the proteins involved in regulating this process. We have focussed on proteins of the MCM or minichromosome maintenance family. These are essential for initiation of DNA replication. They bind to unreplicated DNA, licensing it for one round of DNA replication. DNA replication displaces MCM proteins into the soluble phase of the nucleus and they rebind during mitosis. MCM proteins are DNA helicases that could unwind the two strands of DNA during replication, yet they are not concentrated at replication forks where helicases are expected to be. We have proposed a model of helicase action at a distance from replication forks to reconcile this paradox.
We also study proteins that regulate MCM loading such as Cdc6, Cdt1 and Geminin. We have discovered a new enzyme, MCM3AP, that inhibits DNA replication in vivo and in vitro by acetylating MCM3. We are investigating how this enzyme is regulated and what contribution it makes to controlling cell proliferation. We have shown that Cdc6 has an additional role of regulating cell division, in addition to its role in triggering DNA replication. This raises the possibility that Cdc6 monitors the status of DNA replication to ensure its completion before cell division.
In collaboration with Nick Coleman's group, we are exploring the use of MCM proteins as diagnostic cancer markers to develop non-invasive tests for several of the common cancers.
Selected publications
- Laskey, R.A. and Madine, M.A. (2003) A rotary pumping model for helicase function of MCM proteins at a distance from replication forks. EMBO Rep 4: 26-30.
- Clay-Farrace, L., Pelizon, C., Santamaria, D., Pines, J. and Laskey, R.A. (2003) Human replication protein Cdc6 prevents mitosis through a checkpoint mechanism which implicates Chk1. EMBO J 22: 704-712.
- Takei, Y., Assenberg, M., Tsujimoto, G. and Laskey, R. (2002) The MCM3 acetylase MCM3AP inhibits initiation, but not elongation of DNA replication via interaction with MCM3. J. Biol. Chem. 277: 43121-43125
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