Paul Edwards

Rebecca Fitzgerald

Vincent Gnanapragasam

Phil Jones

Carla Martins

Anna Philpott

Jacqui Shields

Ashok Venkitaraman

Ron Laskey

This page contains research information relating to the work of former MRC CCU Director Professor Ron Laskey, who has now retired from the Unit.

Control of mammalian DNA replication

	A rotary pump model for MCM function. The model proposes that in G1 phase MCM hexamers move along the unreplicated DNA and that in S phase MCMs become immobilised so that the rotary mechanism unwinds the DNA moving it towards replication forks. For details see Laskey and Madine, 2003.

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.

 

Contact

Click here to contact Professor Ron Laskey by email.

 

Recent Publications

	Nuclei (red) that are replicating DNA in vivo continue replication in vitro (yellow) when frozen tissue sections are incubated. Sections are from normal human colon (left) or a colon tumour (right).

Geminin escapes degradation in g1 of mouse pluripotent cells and mediates the expression of oct4, sox2, and nanog. Yang VS, Carter SA, Hyland SJ, Tachibana-Konwalski K, Laskey RA, Gonzalez MA. Curr Biol. 2011 Apr 26;21(8):692-9. Epub 2011 Apr 14.

GANP enhances the efficiency of mRNA nuclear export in mammalian cells. Wickramasinghe VO, Stewart M, Laskey RA. Nucleus. 2010 Jul;1(5):393-396.

MCM3AP is transcribed from a promoter within an intron of the overlapping gene for GANP. Wickramasinghe VO, McMurtrie PI, Marr J, Amagase Y, Main S, Mills AD, Laskey RA, Takei Y. J Mol Biol. 2011 Feb 25;406(3):355-61

mRNA export from mammalian cell nuclei is dependent on GANP. Wickramasinghe VO, McMurtrie PI, Mills AD, Takei Y, Penrhyn-Lowe S, Amagase Y, Main S, Marr J, Stewart M, Laskey RA. Curr Biol. 2010 Jan 12;20(1):25-31.

Improved screening for anal neoplasia by immunocytochemical detection of minichromosome maintenance proteins. Scarpini C, White V, Muralidhar B, Patterson A, Hickey N, Singh N, Mullerat J, Winslet M, Davies RJ, Phillips ML, Stacey P, Laskey RA, Miller R, Nathan M, Coleman N. Cancer Epidemiol Biomarkers Prev. 2008 Oct;17(10):2855-64.

MCM immunocytochemistry as a first line cervical screening test in developing countries: a prospective cohort study in a regional cancer centre in India. Mukherjee G, Muralidhar B, Bafna UD, Laskey RA, Coleman N. Br J Cancer. 2007 Apr 10;96(7):1107-11.

 

To undertake world leading research into cancer cell biology that can be translated into clinical practice to improve the diagnosis and treatment of cancers.