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Organisation of the nucleus during DNA replication
DNA replication is carried out by protein machines that are immobilized at hundreds of sites in the mammalian nucleus. Recruitment of factors and template, their organisation and order of activation are all carefully controlled and coordinated with gene expression. Moreover, synthesis of new DNA from within these factories must be accompanied by formation of new chromatin that, in cycling differentiated cells, bears the same pattern of epigenetic marks as parent cells. These requirements and constraints make the spatial organisation of DNA replication, and its associated events, of fundamental importance to our understanding of both development and disease.
Most of our work is focussed on one protein, CIZ1, which is involved in localization of the cyclin-dependent kinases that regulate DNA replication to their sites of action in the nucleus. We are studying the normal function of CIZ1, the diversity of alternatively spliced forms, and the changes in CIZ1 that occur in human cancers.
We are developing findings that CIZ1B, a variant form, is expressed by lung tumours, and can be found in the blood of people with early stage lung cancer. The potential of this biomarker to become the basis of a blood test for lung cancer is being pursued by University of York spin-out Cizzle Biotech. A permanent research goal is to identify and exploit new factors, including CIZ1B, that might also serve as targets in cancer therapy or as markers of cell proliferation potential.
Recent analyses have implicated CIZ1 in the spatial constraint of Xist long non-coding RNA at the inactivated X chromosome (Xi) in female somatic cells, most likely by anchoring the RNA to the nuclear matrix. Because CIZ1 is a highly abundant and potent marker of the Xi, in addition to being present at many much smaller sites all over the nucleus in male and female cells, we are exploiting the wealth of knowledge that exists about Xi to develop our understanding of the normal function of CIZ1. This has lead to new information about the spatial organisation of chromatin modifying enzymes in normal cells and the role of CIZ1 in delivering template chromatin (Xi) to their sites of action during DNA replication. It has also lead to demonstration of the fragility of the chromatin relocation process and appreciation that cultured cell populations have, like cancer cells, largely bypassed this subtle layer of control. Our main questions now are about the extent to which CIZ1 might contribute to the onset of epigenetic instability in the incipient tumour cell.
As a teacher I aim to give students a framework into which they can slot the knowledge they acquire through reading, and the skills they develop through the program. I want students to be able to understand how different topics interlace to build a comprehensive picture of my area of biology, out of which appreciation of underpinning principles can emerge. It was not until I felt I had 'filled in the gaps' between topics that were taught in isolation during my own education, that new questions began to occur to me. I aim to help my students get to that stage so that their originality can emerge.
I am a mammalian cell biologist mainly, with background in biochemistry (PhD) genetics (BSc) and developmental biology (post-doc) so I tend to teach my subject area from multiple angles, and also to use a range of different techniques in my research. Both are focussed on the functional organisation of the mammalian cell nucleus, the transitions that the nucleus undergoes during the cell cycle and during differentiation, and disruption of its organisation in diseases such as cancer. My main teaching area is cancer biology, which is a vast and fascinating subject that will touch most of us at some points in our lives.
My tutorials often start with an overview of what we do in the lab, as a way to introduce techniques and concepts in mammalian cell biology. This usually results in questions and discussion, and often identifies an area which we choose to investigate further in subsequent sessions. The overall theme is the structure and function of the mammalian cell nucleus which relates to my research on epigenetic control of gene expression. Later in the tutorial set students are encouraged to pick a topic that they are interested in, within this overall theme, and to bring their new knowledge to the group. Tutorials are the most interesting and rewarding of my teaching activities because they can be quite unpredictable, and by the end of a set I feel that I know my students.
Students taking projects in my lab will be working on something related to our ongoing research. We have a wide array of molecular tools that have been developed over the years, including antibodies that can recognise specific alternatively spliced forms of the CIZ1 protein, which plays a role in organising DNA replication in nuclear space. Many of these forms of CIZ1 are linked with disease yet we know very little about them. Projects might use specific antibodies to uncover the expression patterns, interactions and regulation of variants using techniques that include mammalian cell culture, sub-cellular fractionation, quantitative immunofluorescence microscopy or western blot. We also use quantitative gene expression analysis, bioinformatic techniques and many other approaches dictated by the question we are trying to answer.