Cell Division - Iain Hagan

After completing his PhD studies Iain went to Japan on a 4-year postdoctoral fellowship with Professor Mitsuhiro Yanagida in Kyoto University. He returned to the UK in 1993 with a Cancer Research Campaign Return Fellowship to establish a group in The University of Manchester. He continued to work in what later became the Faculty of Life Sciences at The University of Manchester, with further Cancer Research Campaign Fellowship support before moving to the Cancer Research UK Manchester Institute in 2001. In 1999 he was awarded the Human Frontier Science Program 10th Anniversary Medal and in 2001 was the recipient of the BSCB Hooke Medal. Iain is currently a Senior Group Leader at the CRUK MI. In 2009 he was elected to full membership of the European Molecular Biology Organisation (EMBO). In 2016, Iain was awarded a Wellcome Trust Investigator Award to study spatial and temporal control of mitotic commitment.


Cancer is a genetic disease of inappropriate cell proliferation.  Cell proliferation is a balance between increasing cell numbers, through cell division, and reducing them, through cell death.  Within the cell division cycle, the duplication of the genome in S phase is separated from its segregation in mitosis.  A complex structure called the mitotic spindle physically segregates the two genomes in mitosis.  Pathways that promote cell death are initiated when cells enter mitosis with incomplete or damaged DNA, or when they become trapped in mitosis as a consequence of errors in chromosome architecture or spindle function. Because cancers have inherently high levels of genome instability, it is possible to find levels of DNA or spindle damaging agents that can trigger death in tumour cells, while leaving normal tissue untouched.  Anti-mitotics and DNA damaging agents are therefore widely used in the clinic.

We exploit the simplicity and genetic malleability of yeast as a model system in which to identify fundamental principles in the control of the decisions to enter and exit mitosis.  We define the molecular detail of conserved cell cycle controls and key principles of cell division in yeast for subsequent, highly focused, studies in much more complex human cell line models.
There are two principle themes to our research: the role played by the centrosome in promoting mitotic commitment and exit and the properties and control of the protein phosphatases that drive cells out of division. As cell division is accompanied by a cessation of migration and morphogenesis, some of our studies address very specific aspects of cytoskeletal control of morphogenesis.




The inappropriate proliferation of cancer cells can arise from unchecked cell division, a failure to engage cell death pathways, or simultaneous changes in both. Understanding how the diverse cues are integrated to co-ordinate cell division and death is therefore key to understanding the biology of cancer. The DNA damaging approaches of chemotherapy and irradiation owe much of their success to the checkpoint pathways that ensure transition through the cell division cycle only occurs when genome integrity is guaranteed. We study these checkpoint pathways and the control of commitment to the physical process of genome segregation, mitosis. Because the regulatory networks that control cell division are highly conserved, we study these controls in human cells and unicellular fission yeast. The yeast work can identify key questions to ask in the context of complex human cell division cycle control.

Figure 1: The human cell cycle with Cdk1-Cyclin B control of the G2/M transition Passage through the Restriction point (RP) in G1 phase commits a cell to passage through the cell division cycle. DNA replication in S phase is separated from mitosis by a gap phase, G2. Transition through the major rate limiting commitment steps into the cycle, replication and division is driven by Cdk-Cyclin activities.


The cell cycle

In a typical cell division cycle the G1 gap phase precedes DNA replication in S phase, before a second gap phase G2, separates S from genome segregation in Mitosis (M phase) (Figure 1). Growth, developmental and environmental cues determine whether and when a cell leaves the non-cycling G0 state to enter the cell cycle by passing through a decision point of no return in G1 phase called the ‘Restriction point’ (Figure 1). Once cells are through the Restriction point, they are committed to the cycle and progress around the cycle, even if the pro-division cues that pushed them through this regulatory step are removed. Passage through the Restriction point and a second key regulatory step at the G2/M boundary is driven by the activation of distinct CDK-Cyclin protein kinase complexes. Successive waves of Cdk-cyclin activities drive different events as cells transit the cycle (Figure 2). The collective activity of all Cdk-Cyclin kinases must decline to zero in G1 phase because the recruitment of DNA replication proteins to origins of replication is inhibited by Cdk-Cyclin activity. If any Cdk-Cyclin activity persists in this crucial DNA replication licensing window, replication will be defective as some origins will fail to fire and others fire repeatedly.

Cancer and Cdk-Cyclin

In order to inappropriately drive cells through the restriction point and proliferate in the wrong circumstances, cancer cells boost Cdk-Cyclin. However, this de-regulated Cdk-Cyclin activity in the critical replication licensing window, when all Cdk-Cyclin activity should be repressed, causes DNA damage in a phenomenon that is known as ‘oncogene induced replicative stress’ (OIRS). OIRS can raise the degree of damage in cancer cells towards levels that are lethal. This is why the DNA damaging approaches of chemotherapy and radiotherapy are so effective in the clinic: the extra damage from therapy pushes the cancer cells over their lethality threshold.

A cancer’s need to repair more damage than neighbouring tissue places greater reliance upon DNA integrity cell cycle checkpoints that repress Cdk-Cyclin activities to delay cell cycle progression while the damage is repaired. Once the damage is repaired, checkpoint signalling abates and Cdk-Cyclin activity is restored, enabling passage through the cell cycle to re-start. As these pathways are so efficient at blocking division, cancers invariably inactivate the primary DNA damage checkpoint in which p53 blocks passage through the Restriction point. Such p53 deficient cancer cells become entirely reliant upon a second checkpoint at the G2/M boundary. There is therefore considerable therapeutic interest in weakening this second G2/M checkpoint as it will force cancer cells into a lethal division, while their normal neighbours can use their functional p53 checkpoint to pause the cycle when they are damaged.

G2/M transition

The G2/M transition is driven by activation of the Cdk1-Cyclin B protein kinase. Wee1 kinases inhibit Cdk1-Cyclin B by phosphorylating the catalytic Cdk1 subunit. Removal of this phosphate by Cdc25 phosphatases then promotes mitotic entry. A trigger level of Cdk1-Cyclin B activation promotes a positive feedback loop that employs Polo kinase to boost Cdc25 and inhibit Wee1 activities to ensure that mitotic commitment is a rapid and irreversible switch from one state (interphase) into another (division) (Figure 2).

Figure 2: Successive waves of Cdk-Cyclin activity drive cells through the cycle Once cells are driven through the restriction point by Cdk4-Cyclin D and Cdk6-Cyclin D activities, Cdk2-Cyclin E and Cdk2-Cyclin A promote DNA replication. Cdk2-Cyclin A activity persists until the beginning of mitosis, which it triggers alongside the principle mitotic regulator Cdk1-Cyclin B. The absence of any Cdk-Cyclin activity is critical to ensure that the DNA replication complexes can assemble ready for the subsequent division.


The checkpoint pathways that block mitotic commitment when DNA is damaged, or replication is incomplete, do so by boosting the activity of Wee1 family kinases and repressing Cdc25. Thus, when thinking about how to target the G2/M checkpoint, there has been considerable interest in developing drugs that inhibit Wee1. Most of this interest has focused upon the founder member of this kinase family, Wee1. However, while we know a lot about Wee1, we know remarkably little about the biology of the closely related Myt1 kinase. We are therefore investigating how, when and why Myt1 is used to block the commitment to mitosis. Our findings will guide the application of small molecule inhibitors that are currently under development.

Centrosomes and G2/M transition

A second major interest of the team is understanding the role played by the centrosome in regulating the G2/M transition. Centrosomes nucleate all the microtubules in the cell to generate the interphase cytoskeleton and the bipolar mitotic spindle that physically segregates the chromosomes. However, we believe that centrosomes organise more than microtubules. The initial appearance of active Cdk1-Cyclin B on human centrosomes, before propagation throughout the cell, suggests that this organelle provides a specific microenvironment to trigger the G2/M transition. Our studies of the fission yeast centrosome equivalent, the spindle pole body (SPB), provide molecular insight into how and why this switch may operate (Figure 3). We have shown that release of Cdk1-Cyclin B, or Polo kinase activity at the SPB, will drive cells into division.

Figure 3: The fission yeast spindle pole body triggers mitotic commitment Recruitment of PP1 to the SPB component Cut12 determines the level of Polo kinase activity throughout the cell and so sets the threshold for the feedback loops that convert sparks of Cdk1-Cyclin B activity into a mitotic commitment wave that drives cells through division.


In contrast, release of either kinase activity at any other location around the cell has no impact upon division timing. Our attempts to define the molecular basis for such a striking impact have been guided by lessons from the SPB scaffold Cut12. Simply blocking the recruitment of protein phosphatase 1 (PP1) to Cut12 enabled us to delete the cdc25+ gene without compromising viability. This bypass of the requirement for an otherwise essential mitotic inducer arose from the impact of the Cut12/PP1 axis on Polo kinase activity. Polo activity was inappropriately elevated by the abolition of PP1 recruitment to Cut12. We are pursuing the hypothesis that Polo activity overcomes the need for Cdc25 because it boosts Polo’s ability to inhibit Wee1 to such a degree that it completely silences Wee1. In this scenario, the absence of the kinase that places the phosphate onto Cdk1 removes the need for the phosphatase that normally reverses the missing phosphorylation event.

By understanding how the trigger to initiate mitosis is flipped and how cell status can restrain this step, we will gather new insights in how to develop new therapies and optimise the exploitation of existing approaches to treatment options.

Selected Publications


Halova L, Cobley D, Franz-Wachtel M, Wang T, Morrison KR, Krug K, Nalpas N, Maček B, Hagan IM, Humphrey SJ, Petersen J. (2021)
A TOR (target of rapamycin) and nutritional phosphoproteome of fission yeast reveals novel targets in networks conserved in humans.
Open Biology 11(4):200405. PubMed abstract (PMID: 33823663)

Trotter EW, Hagan IM. (2020)
Release from cell cycle arrest with Cdk4/6 inhibitors generates highly synchronized cell cycle progression in human cell culture.
Open Biology 10(10), 200200. PubMed abstract

Chan KY, Alonso-Nuñez M, Grallert A, Tanaka K, Connolly Y, Smith DL, Hagan IM. (2017)
Dialogue between centrosomal entrance and exit scaffold pathways regulates mitotic commitment.
Journal of Cell Biology 216(9):2795-2812. PubMed abstract

Grallert A, Boke E, Hagting A, Hodgson B, Connolly Y, Griffiths JR, Smith DL, Pines J, Hagan IM. (2015)
A PP1-PP2A phosphatase relay controls mitotic progression.
Nature 517(7532):94-8. PubMed abstract

Grallert A, Patel A, Tallada VA, Chan KY, Bagley S, Krapp A, Simanis V, Hagan IM. (2013)
Centrosomal MPF triggers the mitotic and morphogenetic switches of fission yeast.
Nature Cell Biology 15(1):88-95. PubMed abstract

Tallada VA, Tanaka K, Yanagida M, Hagan IM. (2009)
The S. pombe mitotic regulator Cut12 promotes spindle pole body activation and integration into the nuclear envelope.
Journal of Cell Biology 185(5):875-88. PubMed abstract

Petersen J, Hagan IM.  (2005)
Polo kinase links the stress pathway to cell cycle control and tip growth in fission yeast. 
Nature 435(7041):507-12. PubMed abstract

Tanaka K, Petersen J, MacIver F, Mulvihill DP, Glover DM, Hagan IM. (2001)
The role of Plo1 kinase in mitotic commitment and septation in Schizosaccharomyces pombe.
EMBO Journal 20(6):1259-70. PubMed abstract

Hagan I, Yanagida M. (1992)
Kinesin related cut7 protein associates with mitotic and meiotic spindles in fission yeast. 
Nature 356(6364):74-6. PubMed abstract

Hagan I, Yanagida M. (1990)
Novel potential mitotic motor protein encoded by the fission yeast cut7+ gene.
Nature 347(6293):563-6. PubMed abstract

Postdoctoral Fellows
Asma Belbelazi
Daniela Mclaverty
Zoe Edwards
Lenka Halova
Pawan Singh

Scientific Officers
Keren Dawson
Eleanor Wendy Trotter

Graduate Students
Charlie Greenaway-Wells
Alexandra Hendry
Emma Hall