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Philip Zegerman

2017 ZegermanPhilip Zegerman PhD, Wellcome Senior Research Fellow, EMBO Young Investigator, Member of the Department of Biochemistry.

Zegerman Group website | Europe PMC | Pubmed

 

 

 

The regulation of DNA replication initiation in eukaryotes

How is DNA replication controlled? 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.

Selected publications:

• Can G, Kleinert C, Macak D, Zegerman P (2018) Helicase subunit Cdc45 targets the checkpoint kinase Rad53 to both replication initiation and elongation complexes after fork stalling. Molecular Cell, in press.

• Collart C, Smith JC, Zegerman P (2017) Chk1 Inhibition of the Replication Factor Drf1 Guarantees Cell-Cycle Elongation at the Xenopus laevis Mid-blastula Transition. Developmental Cell, 42(1), 82-96.

• 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. elegansJ Cell Biol204, 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 341(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

Zegerman Group 2017

Video: Meet Phil Zegerman

Co-workers

Esther Cabanas Morafraile • Geylani Can • Vincent Gaggioli • Andreas Hadjicharalambous • Fiona Jenkinson • Mark Johnson • Manuela Kieninger • Florence Leroy • Miguel Santos • Shannon Smyly • Kang Wei Tan • Theresa Zeisner