1986 …2019
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Research

How DNA replication is organised and controlled to ensure precise chromosome duplication

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 Xenopuseggs, 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.

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  • 37 Similar Profiles
DNA Replication Medicine & Life Sciences
Licensure Medicine & Life Sciences
Xenopus Medicine & Life Sciences
Replication Origin Medicine & Life Sciences
Cell Cycle Medicine & Life Sciences
Chromatin Medicine & Life Sciences
S Phase Medicine & Life Sciences
Geminin Medicine & Life Sciences

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Projects 2012 2019

Research Output 1986 2018

4 Citations (Scopus)
20 Downloads (Pure)

Histone H4K20 methylation mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing

Shoaib, M., Walter, D., Gillespie, P. J., Izard, F., Fahrenkrog, B., Lleres, D., Lerdrup, M., Johansen, J. V., Hansen, K., Julien, E., Blow, J. J. & Sørensen, C. S., 12 Sep 2018, In : Nature Communications. 9, 1, p. 1-11 11 p., 3704.

Research output: Contribution to journalArticle

Open Access
File
licensing
chromatin
methylation
Methylation
genome
3 Citations (Scopus)
52 Downloads (Pure)

Lgr5+ intestinal stem cells reside in an unlicensed G1 phase

Carroll, T., Newton, I., Chen, Y., Blow, J. & Nathke, I., 7 May 2018, In : Journal of Cell Biology. 217, 5, p. 1667-1685 19 p.

Research output: Contribution to journalArticle

Open Access
File
G1 Phase
Licensure
Stem Cells
Epithelium
Replication Origin
7 Citations (Scopus)
30 Downloads (Pure)

The Anthelmintic Drug Niclosamide and Its Analogues Activate the Parkinson's Disease Associated Protein Kinase PINK1

Barini, E., Miccoli, A., Tinarelli, F., Mulholland, K., Kadri, H., Khanim, F., Stojanovski, L., Read, K. D., Burness, K., Blow, J. J., Mehellou, Y. & Muqit, M. M. K., 2 Mar 2018, In : ChemBioChem. 19, 5, p. 425-429 5 p.

Research output: Contribution to journalArticle

Open Access
File
Niclosamide
Anthelmintics
Protein Kinases
Parkinson Disease
Mitochondrial Membrane Potential
23 Citations (Scopus)
52 Downloads (Pure)

Reversal of DDK-mediated MCM phosphorylation by Rif1-PP1 regulates replication initiation and replisome stability independently of ATR/Chk1

Alver, R. C., Chadha, G. S., Gillespie, P. J. & Blow, J. J., 7 Mar 2017, In : Cell Reports. 18, 10, p. 2508-2520 13 p.

Research output: Contribution to journalArticle

Open Access
File
Protein Phosphatase 1
Phosphorylation
Multicarrier modulation
Phosphotransferases
DNA Replication
2 Citations (Scopus)
40 Downloads (Pure)

The High-Affinity Interaction between ORC and DNA that Is Required for Replication Licensing Is Inhibited by 2-Arylquinolin-4-Amines

Gardner, N. J., Gillespie, P. J., Carrington, J. T., Shanks, E. J., McElroy, S. P., Haagensen, E. J., Frearson, J. A., Woodland, A. & Blow, J. J., 17 Aug 2017, In : Cell Chemical Biology. 24, 8, p. 981-992.e4 16 p.

Research output: Contribution to journalArticle

Open Access
File
Origin Recognition Complex
Licensure
Amines
DNA
Minichromosome Maintenance Proteins

Prizes

British Association for Cancer Research / Zeneca "Young Scientist of the Year"

Julian Blow (Recipient), 1996

Prize: Prize (including medals and awards)

Fellow of the Academy of Medical Sciences

Julian Blow (Recipient), 2012

Prize: Election to learned society

Fellow of the Royal Society of Edinburgh

Julian Blow (Recipient), 2002

Prize: Election to learned society

Lister Institute Jenner-Centenary Research Fellow (1991-1996)

Julian Blow (Recipient), 1991

Prize: Fellowship awarded competitively

Member of the European Molecular Biology Organization

Julian Blow (Recipient), 1999

Prize: Election to learned society

Activities 1997 2012

7th Cold Spring Harbor Laboratory Meeting on Dynamic Organization of Nuclear Function

J. Julian Blow (Chair)
27 Sep 20121 Oct 2012

Activity: Participating in or organising an event typesParticipation in conference

DNA Replication of Eukaryotic Genomes

J. Julian Blow (Invited speaker)
2 Jul 20127 Jul 2012

Activity: Participating in or organising an event typesParticipation in conference

European Research Council (External organisation)

J. Julian Blow (Member)
2012

Activity: Membership typesMembership of committee

National University of Ireland, Galway (External organisation)

J. Julian Blow (Chair)
2012

Activity: Membership typesMembership of panel

Thesis

An investigation into the regulation of replication factories and dormant origins in human cells

Author: McIntosh, D., 2014

Supervisor: Blow, J. (Supervisor)

Student thesis: Doctoral ThesisDoctor of Philosophy

Consequences of partial chromosome re-replication in mammalian cells

Author: Klotz-Noack, K., 2013

Supervisor: Blow, J. (Supervisor)

Student thesis: Doctoral ThesisDoctor of Philosophy

File

Investigating the Mechanism of Geminin Inactivation

Author: Creavin, K., 2015

Supervisor: Blow, J. (Supervisor)

Student thesis: Doctoral ThesisDoctor of Philosophy

File

Post-Replicative Resolution of Under-Replication

Author: Carrington, J. T., 2017

Supervisor: Blow, J. (Supervisor)

Student thesis: Doctoral ThesisDoctor of Philosophy

File

Spatiotemporal dynamics of cell division in intestinal homeostasis

Author: Carroll, T. D., 2016

Supervisor: Nathke, I. (Supervisor) & Blow, J. (Supervisor)

Student thesis: Doctoral ThesisDoctor of Philosophy