Our research


We study how cells make a perfect copy of the genome, a process called DNA replication. Failures in this process are the root cause of many diseases, particularly cancers, and inhibitors of DNA replication are frequently used in the clinic as anti-viral agents and chemotherapies. Our studies shed light on the consequences of these drugs for cell division control.


DNA replication control during the cell cycle

It is vitally important that the entire genome is copied perfectly in every cell division. Failures in this copying process – termed DNA replication – result in mutations that are the root cause of cancers. In our lab we study how perfect DNA replication is achieved during a single cell cycle. We work primarily with the budding yeast Saccharomyces cerevisiae and we apply our findings to other systems including cancer cells.


DNA damage and genome stability

featured-image

Difficulties during genome duplication, such as a lack of metabolites, are a common feature of cancer and ageing cells. Such replication stress activates a checkpoint kinase response, which is essential for rescuing genome duplication and are an active area of interest for the development of new chemotherapeutic agents. We are interested in understanding the mechanisms and functions of this checkpoint kinase response.


Genome duplication and development

Healthy tissues coordinate cell proliferation with differentiation and for many cell types this involves dramatic changes in genome duplication. The mechanisms and physiological importance of these changes in DNA replication are very poorly understood. We study C. elegans and Xenopus embryos to understand the function of S-phase control during healthy animal development.


Public engagement and outreach

Phil Zegerman at Kettle's Yard for the Antony Gormley exhibition

As part of the University of Cambridge and Wellcome Trust commitment to public engagement and widening participation, we are actively involved in school visits and public interactions with our research. Here is a picture of Philip Zegerman before giving a talk at the Antony Gormley exhibition at Kettle’s yard.


Publications

Checkpoint inhibition of origin firing prevents inappropriate replication outside of S-phase.

eLife (2021).

Johnson MC, Can G, Santos MM, Alexander D, and Zegerman P.

This study redefines the scope and specificity of the ‘S-phase checkpoint’ with implications for understanding the roles of this checkpoint in the majority of cancers that lack proper cell cycle controls.


Identification of the critical replication targets of CDK reveals direct regulation of replication initiation factors by the embryo polarity machinery in C. elegans.

PLOS Genetics (2020).

Gaggioli V, Kieninger MR, Klunicka A, Butler R, and Zegerman P.

This study provides the first direct molecular mechanism through which polarization of the embryo is coordinated with DNA replication initiation factors


Checkpoint inhibition of origin firing prevents topological stress.

Genes & Development (2019).

Morafraile EC, Hänni C, Allen G, Zeisner T, Clarke C, Johnson MC, Santos MM, Carroll L, Minchell NE, Baxter J, Banks P, Lydall D, Zegerman P.

Explains the consequences of loss of checkpoint function for a novel form of replication stress, which may be relevant to the combinatorial treatment of cancers with checkpoint and topoisomerase inhibitors.

...

Helicase subunit Cdc45 targets the checkpoint kinase Rad53 to both replication initiation and elongation complexes after fork stalling.

Molecular Cell (2018).

Can G, Kauerhof AC, Macak D, Zegerman P.

Provides molecular mechanism for how the replication checkpoint kinases coordinate different steps of DNA replication. Inhibitors of these kinases are in clinical trials as chemotherapies.

...

Chk1 inhibition of the replication factor Drf1 guarantees cell-cycle elongation at the Xenopus laevis mid-blastula transition.

Developmental Cell (2017).

Collart C, Smith JC, Zegerman P.

Describes the first essential role for checkpoint kinases in cell cycle control during vertebrate embryogenesis. Chk1 delays cell cycle progression by inhibiting replication initiation through degradation of Drf1.

...

Terminating the replication helicase.

Nature Cell Biology (2017).

Gaggioli V, Zegerman P.


Sperm is epigenetically programmed to regulate gene transcription in embryos.

Genome Research (2016).

Teperek M, Simeone A, Gaggioli V, Miyamoto K, Allen GE, Erkek S, Kwon T, Marcotte EM, Zegerman P, Bradshaw CR, Peters AH, Gurdon JB, Jullien J.


Evolutionary conservation of CDK targets in eukaryotic DNA replication initiation.

Chromosoma (2015).

Zegerman, P.


CDK phosphorylation of SLD-2 is required for replication initiation and germline development in C. elegans.

Journal of Cell Biology (2014).

Gaggioli, V, Zeiser, E, Rivers, D, Bradshaw, CR, Ahringer, J, and Zegerman, P. (2014).

Characterises the first essential CDK substrate required for replication initiation in a metazoan system.


DNA replication: polymerase epsilon as a non-catalytic converter of the helicase.

Current Biology (2013).

Zegerman, P.


Titration of four replication factors is essential for the Xenopus laevis midblastula transition.

Science (2013).

Collart, C, Allen, GE, Bradshaw, CR, Smith, JC, and Zegerman, P.

Provides molecular proof for the 30 year old Newport and Kirschner model for control of cell cycle length during embryogenesis. Highlighted in Nature Reviews Genetics 2013 Sep;14(9):598 and F1000.


DNA replication checkpoint signaling depends on a Rad53-Dbf4 N-terminal interaction in Saccharomyces cerevisiae.

Genetics (2013).

Chen, YC, Kenworthy, J, Gabrielse, C, Hanni, C, Zegerman, P, and Weinreich, M.


Quantitative proteomics reveals the basis for the biochemical specificity of the cell-cycle machinery.

Molecular Cell (2011).

Pagliuca, FW, Collins, MO, Lichawska, A., Zegerman, P, Choudhary, JS, and Pines, J.


Limiting replication initiation factors execute the temporal programme of origin firing in budding yeast.

EMBO Journal (2011).

Mantiero, D, Mackenzie, A, Donaldson, A, and Zegerman, P.

Establishes a mechanism for the temporal firing of origins during S-phase and shows for the first time in any system that the temporal programme of origin firing is essential. Recommended in F1000.


Checkpoint-dependent inhibition of DNA replication initiation by Sld3 and Dbf4 phosphorylation.

Nature (2010).

Zegerman, P, and Diffley, JF.

Provides the molecular mechanism for the long-standing question of how checkpoint kinases inhibit DNA replication. This work is recommended in F1000.


DNA replication as a target of the DNA damage checkpoint.

DNA Repair (2009).

Zegerman, P, and Diffley, JF.


Phosphorylation of Sld2 and Sld3 by cyclin-dependent kinases promotes DNA replication in budding yeast.

Nature (2007).

Zegerman, P, and Diffley, JF.

Describes how CDK controls replication initiation in budding yeast. Highlighted in Nature 2007 Jan 18;445(7125):272-4 This work is recommended in F1000.


Lab members

Philip Zegerman

Group Leader

I did my PhD on chromatin biology in human cells in Cambridge and a postdoc in London with John Diffley on DNA replication control in yeast. My job is to keep everyone happy.

Mark Johnson

Lab Manager

I am interested in the interplay of replication timing, transcription and chromatin dynamics and how these interactions are orchestrated.

Fiona Jenkinson

PhD Student

I study the cell cycle control of DNA replication - what regulates when and where it takes place? and at what speed?

Miguel Santos

PhD Student

I am studying the role of the temporal order of DNA replication in transcription and chromatin organisation using yeast genetics and bioinformatics. I am also the lab’s Star Wars #1 fan.

Andreas
Hadjicharalambous

PhD Student

I am interested in understanding the role of checkpoint kinases play at stalled replisomes during S-phase replication stress.
I have failed to pass the Turing test twice.

Ivan Phanada

MPhil Candidate

I explore the way phosphorylation coordinates DNA replication with the cell cycle, and the mechanistic interplay to keep that in check.
I rock-climb competitively!

Ellie Stuart

Part III Student

I am studying the effects of the anti-viral drug ribavirin on DNA replication – how does it inhibit DNA replication and how does this affect genome stability?

Luke

The lab's mascott

Makes friends with everyone at the pub.
Favourite quote: “Luke, I am your father.”
Favourite food: YOURS!


Lab photo gallery


Funding

Wellcome logo EMBO YIP logo CRUK logo MRC logo AstraZeneca logo BBSRC logo

Join us

Informal inquiries can be made at any time to p.zegerman_at_gurdon.cam.ac.uk


Contact us

Contact us:
Wellcome Trust/Cancer Research UK Gurdon Institute
Tennis Court Road
Cambridge CB2 1QN, UK
p.zegerman_at_gurdon.cam.ac.uk