Philip Zegerman PhD, Wellcome Trust Senior Research Fellow, Member of the Department of Biochemistry.
The regulation of DNA replication initiation in eukaryotes
A fundamental requirement for all life on earth is that an exact copy of the entire genome must be made before cell division. DNA replication is therefore tightly regulated because failures in this process cause genomic instability, which is a hallmark of many diseases, most notably cancers. In addition, inhibition of DNA replication is the primary mode of action of many anti-tumour therapies.
Therefore investigating DNA replication control is important for finding new ways to diagnose and treat cancers. The evolutionary conservation of DNA replication mechanisms allows us to study this process in multiple systems, facilitating the translation of findings to humans.
We have shown that the levels of several key replication factors are critical to control the rate of genome duplication, not only in the single-celled organism, budding yeast, but also during vertebrate development in frog embryos. Our studies demonstrate that regulation of the levels of these factors is vital not only for normal cell division, but also for regulating the rate of cell proliferation in animal tissue. This has important implications for the deregulation of cell proliferation, which occurs in cancers.
• Gaggioli V, Zeiser E, Rivers D, Bradshaw CR, Ahringer J and Zegerman P (2014) CDK phosphorylation of SLD-2 is required for replication initiation and germline development in C. elegans. J Cell Biol 204, 507-522
• Collart C, Allen GE, Bradshaw CR, Smith JC, Zegerman P (2013) Titration of four replication factors is essential for the Xenopus laevis midblastula transition. Science Vol. 341 no. 6148, 893-896
• Mantiero D, Mackenzie A, Donaldson A and Zegerman P (2011) Limiting factors execute the temporal programme of origin firing in budding yeast. EMBO J, 23, 4805-4814
• Walton-Pagliuca F, Collins M, Zegerman P, Choudhary J and Pines J (2011) Quantitative proteomics reveals the basis for the biochemical specificity of the cell cycle machinery. Molecular Cell, 43, 406-417
• Zegerman P and Diffley JF (2010) Checkpoint dependent inhibition of DNA replication initiation via phosphorylation of Sld3 and Dbf4. Nature, 467, 474-478
• Zegerman P and Diffley JF (2007) Phosphorylation of Sld2 and Sld3 by cyclin-dependent kinases promotes DNA replication in budding yeast. Nature, 445, 281-285