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. Failures in DNA replication 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. Understanding DNA replication control is therefore 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.
Research objectives
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What mechanisms control the rate of DNA synthesis in S-phase?
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What are the physiological roles of regulation of S-phase length?
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How do errors in DNA replication contribute to the mutations observed in cancer cells?
Key publications
Morafraile EC, Hänni C, Allen G, Zeisner T, Clarke C, Johnson MC, Santos MM, Carroll L, Minchell NE, Baxter J, Banks P, Lydall D, Zegerman P (2019). Checkpoint inhibition of origin firing prevents DNA topological stress. Genes Dev., 33(21-22):1539-1554. doi: 10.1101/gad.328682.119
Can G, Kauerhof AC, Macak D, Zegerman P (2019). Helicase subunit Cdc45 targets the checkpoint kinase Rad53 to both replication initiation and elongation complexes after fork stalling. Mol. Cell, 73(3):562-573. doi: 10.1016/j.molcel.2018.11.025
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. Dev. Cell, 42(1):82-96. doi: 10.1016/j.devcel.2017.06.010
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. doi: 10.1126/science.1241530
Mantiero D, Mackenzie A, Donaldson A, Zegerman P (2011). Limiting replication initiation factors execute the temporal programme of origin firing in budding yeast. EMBO J., 30(23):4805-4814. doi: 10.1038/emboj.2011.404
Philip Zegerman