Professor Julian Blow FRSE FMedSci
Chromosome replication is a key event in the eukaryotic cell division cycle. During S phase the entire genome must be faithfully duplicated with the minimum of errors. The many thousands of replication forks involved in this process must be co-ordinated to ensure that despite the very large quantities of DNA involved, no section of DNA is left unreplicated and no section of DNA is replicated more than once. Cells achieve this by having a distinct stage that occurs prior to S phase when replication origins are "licensed" for replication. At the onset of S phase, replication forks are initiated only at these licensed replication origins. As initiation occurs at each origin, the licence is removed, thereby ensuring that it fires only once in each cell cycle. Mistakes made in this process may cause irreversible genetic modifications that could ultimately lead to the cells becoming cancerous. Many early stage cancer cells have lost the ability to correctly down-regulate the licensing system, suggesting that it is an important control system for cancer cells to evade.
The aim of our work is to understand at a molecular level the way that chromosome replication is regulated, and to apply this knowledge to improving the diagnosis and treatment of cancer. We use a number of two main model systems to study cell cycle control of DNA replication. Cell-free extracts of Xenopus eggs, which support all the nuclear events of the early embryonic cell cycle, provide a powerful system for studying DNA replication control at a biochemical level. We also use human tissue culture cells which have important advantages for studying DNA replication using cell biological and molecular genetic approaches. Current research projects are addressing: a) how the licensing system is regulated at different stages of the cell division cycle; b) how the Cdc7 and cyclin-dependent kinases trigger the initiation of DNA replication; c) how replication origins are physically organised on chromosomal DNA; and d) the potential of small molecule inhibitors of replication licensing to provide a novel anti-cancer treatment.
Gardner, N.J., Gillespie, P.J., Carrington, J.T., Shanks, E.J., McElroy, S.P., Haagensen, E.J., Frearson, J.A., Woodland, A. and Blow, J.J. (2017). The high-affinity interaction between ORC and DNA that is required for replication licensing is inhibited by 2-Arylquinolin-4-amines. Cell Chem Biol 24, 981–992 view paper
Alver, R.C., Chadha, G.S., Gillespie, P.J. and Blow, J.J. (2017) Reversal of DDK-mediated MCM phosphorylation by Rif1-PP1 restrains initiation of DNA replication in vertebrates. Cell Reports 8, 2508-2520. view paper
Moreno, A., Carrington, J.T., Albergante, L., Al Mamum, M., Haagensen, E.J., Komseli, E.-S., Gourgolis, V.G., Newman, T.J. and Blow, J.J. (2016) Unreplicated DNA remaining from unperturbed S phases passes through mitosis for resolution in daughter cells. Proc Natl Acad Sci USA 113, E5757-64. view paper
Sonneville, R., Craig, G., Labib, K., Gartner, A. and Blow, J.J. (2015) Both Chromosome Decondensation and Condensation Are Dependent on DNA Replication in C. elegans Embryos. Cell Rep. 12, 405-17. view paper
Albergante, L., Blow, J.J. and Newman, T.J. (2014) Buffered Qualitative Stability explains the robustness and evolvability of transcriptional networks. eLife, 3: e02863. view paper
Poh, W.T., Singh Chadha, G., Gillespie, P.J., Kaldis, P. and Blow, J.J. (2014) Xenopus Cdc7 executes its essential function early in S phase and is counteracted by checkpoint-regulated Protein Phosphatase 1. Open Biology 4: 130138. view paper