About the Project
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.
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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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