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Regulation of replication machinery disassembly


Institute of Cancer and Genomic Sciences

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Dr A Gambus , Dr M Saponaro No more applications being accepted Competition Funded PhD Project (European/UK Students Only)

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 extensive mass spectrometry analyses of the post-termination replication machinery and whole chromatin upon inhibition of replisome dissolution provides us with potential candidates for modifying enzymes or factors regulating its disassembly or replication fork termination.

This project aims at characterisation of the function and importance of these candidates in process of replication machinery disassembly. The studies will be performed to start with in cell free system of Xenopus laevis egg extract and the findings obtained will be then translated to human immortalised 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.

More details of the project can be found at:
https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/structural_biology/disassembly

Funding Notes

Funding notes:
This project is funded through MIBTP training programme. Funding provided is for student fees at UK/home level, studentship and bench fees.
For details of the training programme and how to apply please visit:
https://www.birmingham.ac.uk/research/activity/mibtp/index.aspx
https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/
Please note that you need to apply through both Warwick website to access MIBTP application and Birmingham website to access University of Birmingham PhD application.

References

1. Priego Moreno S*, Bailey R*, Campion N, Herron S, Gambus A. Polyubiquitylation drives replisome disassembly at the termination of DNA replication. Science, 2014 Oct 24;346(6208):477-81. doi: 10.1126/science.1253585.
2. Moreno SP, Gambus A. Mechanisms of eukaryotic replisome disassembly. Biochem Soc Trans. 2020 Jun 30;48(3):823-836. doi: 10.1042/BST20190363
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