PhD Research Project

Joseph Yeeles

Structural and mechanistic investigations of the human chromosome replication machinery

Joseph Yeeles

Accurate genome duplication is essential for all forms of life. The molecular machinery that orchestrates this process is collectively termed the replisome — a complex assembly of molecular machines that coordinates DNA template unwinding, DNA synthesis, histone transfer and other replication-coupled processes, including a variety of DNA repair mechanisms. This is an exceptionally exciting time for DNA replication research, driven by recent advances in replisome reconstitution, cryo-EM structure determination and DNA sequencing approaches.

Our group has pioneered several of the key advances driving this field forward, combining biochemical reconstitution, functional DNA replication assays and structural biology to investigate replisome structure, function and mechanism. We achieved the first reconstitution of functional human replisomes from purified proteins and have since determined several human replisome structures by cryo-EM. Building on this platform, we will spend the coming years watching the human replication machinery in action — capturing, at near-atomic resolution, how it is assembled, how it navigates the genome during normal DNA replication and how it responds when it collides with obstacles such as DNA damage and protein barriers.

We are seeking an ambitious and enthusiastic PhD student to join our research group and undertake a project addressing a key, currently unresolved question in human replisome function. You will gain extensive experience in protein purification, complex biochemical reconstitution and structural biology, particularly cryo-EM. We are a medium-sized, open and collaborative group: everyone works closely together, ideas and troubleshooting are shared freely across the group and you’ll be supported to learn new techniques directly at the bench rather than working in isolation. This hands-on culture provides an excellent environment in which to develop as an independent researcher while always having supportive and knowledgable colleagues close at hand.

Relevant Reading

How Pol α-primase is targeted to replisomes to prime eukaryotic DNA replicationJones ML, Aria V, Baris Y, Yeeles JTPMolecular Cell 83(16): 2911-2924.e16 (2023)
Fast and efficient DNA replication with purified human proteinsBaris Y, Taylor MRG, Aria V, Yeeles JTPNature 606(7912): 204-210 (2022)
A conserved mechanism for regulating replisome disassembly in eukaryotesJenkyn-Bedford M, Jones ML, Baris Y, Labib KPM, Cannone G, Yeeles JTP, Deegan TDNature 600(7890): 743-747 (2021)

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