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 different 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 then apply insights gained from the Xenopus system to the study of replication in human tissue culture cells which have important advantages for studying DNA replication using cell biological and molecular genetic approaches. We are also using C. elegans as a model system to study DNA replication in a genuine physiological setting. 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) the way that replication is co-ordinated with other cell cycle events; d) how replication origins are physically organised on chromosomal DNA; and e) how different cellular stresses affect the replication programme through checkpoint signals.
Singh Chadha, G. and Blow, J.J. (2016).
Xenopus Mcm10 is a CDK-substrate required for replication fork stability. Cell Cycle, in press
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. 2015 Jul 21;12(3):405-17. doi: 0.1016/j.celrep.2015.06.046
Epub 2015 Jul 9. PMID: 26166571 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
Newman, T. J., Mamun, M. A., Nieduszynski, C. A. and Blow, J.J. (2013)
Replisome stall events have shaped the distribution of replication origins in the genomes of yeasts. Nucleic Acids Res 41, 9705-9718. (PMID:23963700) View Paper
Klotz-Noack, K., McIntosh, D., Schurch, N., Pratt, N. and Blow, J.J. (2012)
Re-replication induced by geminin depletion occurs from G2 and is enhanced by checkpoint activation. J. Cell Sci 125, 2436-2445. View Paper
Sonneville, R., Querenet, M., Craig, A., Gartner, A. and Blow, J.J. (2012)
The dynamics of replication licensing in live C. elegans embryos. J. Cell Biol 196, 233-246 View Paper
Kisielewska, J. and Blow, J.J. (2012). Dynamic interactions of high Cdt1 and geminin levels regulate S phase in early Xenopus embryos. Development 139, 63-74. View Paper
Blow, J. J., Ge, X.Q. and Jackson, D.A. (2011) How dormant origins promote complete genome replication. Trends Biochem Sci 36, 405-414. PMID: 21641805 View Paper
Gambus, A., Khoudoli, G.A., Jones, R.C. and Blow, J.J. (2011). Mcm2-7 form double hexamers at licensed origins in Xenopus egg extract. J. Biol. Chem. 286, 11855-11864. View Paper