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Regulation of eukaryotic DNA replication by DONSON

Institute of Cancer and Genomic Sciences

About the Project

DNA replication is precisely regulated as unrepaired errors can lead to severe consequences, such as genetic disease, cancer and premature ageing. Surprisingly, despite six decades of research little was known about the termination stage of eukaryotic replication. The Gambus lab recently provided a much-needed breakthrough in this field and since then has characterised the first elements of the replication machinery (replisome) disassembly mechanism. Moreover, preliminary data from the Gambus lab indicate that perturbations of this process can lead to DNA damage. The perfect execution of the termination stage of DNA replication is therefore equally essential as initiation and elongation for maintenance of the stability of our genomes. However, our knowledge of this process is very limited.

Our recent analysis of the proteome associated with the post-termination replisome identified DONSON as a major component. DONSON is a novel human disease gene mutated in patients with microcephalic primodial dwarfism. DONSON ensures replication fork stability and promotes checkpoint activation when replication forks stall. In support of this, DONSON mutations are found in a variety of cancer types. However, the mechanism with which DONSON functions to protect DNA replication/genome stability remains to be defined.
To define the molecular function of DONSON during DNA replication, we will use Xenopus laevis egg extract replication system, which provides a robust cell-free system that can sustain a whole round of DNA replication in a tube. It can be readily manipulated, such that specific proteins depleted/added back in quick and controlled manner. We therefore plan to initially use this system and then recapitulate our findings in patient-derived cell lines.

Techniques used: Recombinant protein production; Protein biochemistry: in vitro, in extracto and in vivo; Electron microscopy and single molecule microscopy; Cell biology – fluorescent microscopy, survival etc.

Funding Notes

Funding notes: this project is available to students with their own funding.
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Moreno, S. P., Bailey, R., Campion, N., Herron, S., and Gambus, A. (2014) Polyubiquitylation drives replisome disassembly at the termination of DNA replication. Science 346, 477-481

Reynolds, J. J., Bicknell, L. S., Carroll, P., Higgs, M. R., Shaheen, R., Murray, J. E., Papadopoulos, D. K., Leitch, A., Murina, O., Tarnauskaite, Z., Wessel, S. R., Zlatanou, A., Vernet, A., von Kriegsheim, A., Mottram, R. M., Logan, C. V., Bye, H., Li, Y., Brean, A., Maddirevula, S., Challis, R. C., Skouloudaki, K., Almoisheer, A., Alsaif, H. S., Amar, A., Prescott, N. J., Bober, M. B., Duker, A., Faqeih, E., Seidahmed, M. Z., Al Tala, S., Alswaid, A., Ahmed, S., Al-Aama, J. Y., Altmuller, J., Al Balwi, M., Brady, A. F., Chessa, L., Cox, H., Fischetto, R., Heller, R., Henderson, B. D., Hobson, E., Nurnberg, P., Percin, E. F., Peron, A., Spaccini, L., Quigley, A. J., Thakur, S., Wise, C. A., Yoon, G., Alnemer, M., Tomancak, P., Yigit, G., Taylor, A. M., Reijns, M. A., Simpson, M. A., Cortez, D., Alkuraya, F. S., Mathew, C. G., Jackson, A. P., and Stewart, G. S. (2017) Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nat Genet 49, 537-549

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