We are excited to advertise this Edinburgh Doctoral College Scholarship for the Institute of Genetics and Cancer.
Further details of the scheme and application process can be found at https://www.ed.ac.uk/institute-genetics-cancer/igc-graduate-research-and-training/edinburgh-college-doctoral-scholarship-projects
Project Description:
DNA replication is driven by a molecular machine called the replisome, which is assembled at tens of thousands of genomic loci called DNA replication origins in every cell cycle. Every time two replisomes emanating from neighbouring replication origins converge and meet one another, DNA replication terminates, leading to the local completion of DNA synthesis, and replisome disassembly. The faithful termination of DNA replication is fundamental for cellular fitness, as a failure to replicate even a short stretch of DNA would lead to chromosomal instability in mitosis, or else might activate more mutagenic forms of DNA synthesis.
In recent years, we have advanced our molecular understanding of this enigmatic process in the simple budding yeast model system (Deegan et al. Mol. Cell, 2019; Deegan et al., eLife, 2020; Jenkyn-Bedford et al., Nature, 2021). Crucially, however, the molecular mechanisms of replication termination, and ways in which defective termination drives genome instability, remain poorly characterised in human cells. This might be particularly relevant at Common Fragile Sites (CFSs), which frequently fail to complete DNA replication before mitosis, and are key hotspots for genome instability in human cancers.
We now aim to interrogate the molecular mechanisms of DNA replication termination in human cells. Inspired by our previous work with budding yeast, the successful candidate will develop new systems that recapitulate DNA replication termination in vitro with purified human proteins. This work will be complemented by proteomic screens to identify new termination factors (with Alex Von Kriegsheim), and cell biology experiments to investigate links between defective termination and chromosomal instability in human cells (with Nick Gilbert).
As well as being an exciting project in a fundamental and understudied area of human chromosome biology, this work will also be important for our understanding of a number of human diseases in which replication termination factors are mutated.
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