研究领域

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Our main goal is to identify and exploit new factors that might serve as targets in cancer therapy or as markers of cell proliferation potential. To achieve this we are investigating the functional organisation of the mammalian cell nucleus, and the transitions that this undergoes during cell differentiation and passage through the cell cycle. We are focused on the temporal and spatial organization of DNA replication and related processes, by studying the relationship between replication proteins, chromatin, RNA and the insoluble structural framework referred to as the nuclear matrix (Fig. 1). In mammalian somatic cells cyclin-dependent initiation involves spatially constrained assembly of replication proteins inside the nucleus during G1 phase of the cell cycle, followed by their activation to begin DNA synthesis. In recent years we have studied the MCM protein complex, which becomes briefly attached to the nuclear matrix just before DNA replication begins (Hesketh et al 2015), the cyclins themselves (Munkley et al 2011), and the cyclin-interacting protein CIZ1 (Copeland et al 2015). Cyclin E is spatially constrained in fundamentally different ways in cell types that retain the capacity to change (stem and progenitor cells) compared to those that have a defined identity, suggesting a fundamental transition in the way that regulatory factors access their targets during differentiation. We also showed that cancer cells are similar to stem cells in this respect, having spatially unconstrained replication proteins. Heritable changes in gene expression are accompanied by epigenetic modifications of DNA or chromatin, but our data suggests that epigenetic information may also be specified in somatic cells by immobilization of DNA replication on the nuclear-matrix, facilitating the formation of a constrained genomic arrangement. We have found that this level of control is compromised in cancer cells likely contributing to their plasticity and failure to maintain epigenetic control of gene expression.