MRC Human Genetics Unit
Medical Research Council Human Genetics Unit

Tom Deegan Research Group

Mechanism and Regulation of Chromosome Replication

Dr Tom Deegan, Programme Leader Track
Dr Tom Deegan, Programme Leader Track

Section: Genome Regulation

Research in a Nutshell 

Every time a cell divides, it must precisely replicate every one of its chromosomes once, before dividing the replicated chromosomes equally between the new daughter cells. Our lab is interested in understanding the fundamental mechanisms that cells use to replicate their chromosomes, and how these mechanisms contribute to stable genome inheritance between cells and between generations.

Chromosome replication is carried out by a highly complex molecular machine called the replisome, which is assembled from over 30 individual protein components. To understand the mechanism and regulation of this remarkable machine in molecular detail, we build the replisome in a test tube from individually purified components. We also complement the use of this highly defined in vitro system with molecular genetic and cryo-electron microscopy approaches.

We have previously exploited these approaches to decipher the final (termination) phase of replication, including the molecular mechanism of replisome disassembly, and how this process is regulated to prevent premature disassembly at active replication forks. We are currently exploring instances in which replisome disassembly might be triggered prematurely, as well as other mechanisms of replication termination. We also plan to develop new biochemical systems that recapitulate the unique events that occur during chromosome replication in meiosis. Ultimately our work will give a detailed picture of how cells replicate their chromosomes normally, and how this process goes wrong in human diseases such as cancer and developmental disorders.

People

Tom Deegan Group Leader

Contact

T.Deegan@ed.ac.uk

Publications

  • Jenkyn-Bedford, M., Jones, M.L., Baris, Y., Labib, K.P.M., Cannone, G., Yeeles, J.T.P*., Deegan, T.D*. A Conserved Mechanism for Regulating Replisome Disassembly in Eukaryotes. Nature (2021). https://doi.org/10.1038/s41586-021-04145-3 *Co-corresponding
  • Deegan, T.D.*, Mukherjee, P, Fujisawa, R, Polo Rivera, C, Labib, K.P.M.* (2020) CMG helicase disassembly is controlled by replication fork DNA, replisome components and a ubiquitin threshold. eLife 2020;9:e60371. *Co-corresponding authors.
  • Deegan, T.D.*, Baxter, J, Ortiz-Bazan, M.A., Yeeles, J.T.P., Labib, K.P.M.* (2019) Pif1-Family Helicases Support Fork Convergence during DNA Replication Termination in Eukaryotes. Mol Cell. 74, 231-234. *Co-corresponding authors.
  • Deegan, T.D., Yeeles, J.T., Diffley, J.F. (2016) Phosphopeptide binding by Sld3 links Dbf4-dependent kinase to MCM replicative helicase activation. EMBO J. 35(9): 961-973. PMID: 26912723.
  • Deegan, T.D., Diffley, J.F. (2016) MCM: one ring to rule them all. Curr Opin Struct Biol. 37, 145-151.
  • Yeeles, J.T., Deegan, T.D., Janska, A, Early, Diffley, J.F. (2015) Regulated eukaryotic DNA replication origin firing with purified proteins. Nature. 519, 431-435.

Collaborations

  • Dr Joe Yeeles, MRC LMB, Cambridge
  • Dr Jon Baxter, University of Sussex

Partners and Funders

  • Medical Research Council

Scientific Themes

Chromosome replication, Genome stability

Technology Expertise

Protein and nucleic acid biochemistry, in vitro reconstitution, yeast molecular biology and genetics