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Structure and mechanisms of the eukaryotic replisome

  • Full or part time
  • Application Deadline
    Tuesday, December 03, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description


Each time a cell divides it must duplicate its genetic material. The extraordinary molecular machine responsible for this task is called the replisome. The replisome is one of the largest, most complex and highly regulated machines in the cell. At is core is the 11-subunit replicative CMG (Cdc45-MCM-GINS) helicase. Assembly and activation of CMG is the key step in building a replisome. As a post doc I reconstituted this process with purified proteins for the first time1, which marked the beginning of a new era in the study of eukaryotic chromosome replication.

After CMG is activated, numerous additional proteins (at least 10) associate with it to form the replisome. However, the molecular mechanisms of many of these proteins are not well understood because currently there are no published high-resolution structures of any of them bound to CMG. My lab has recently obtained near atomic resolution structures of CMG bound to several replisome proteins. This has provided many novel insights into how these proteins synergise with CMG to facilitate replisome progression.

We are looking for an ambitious and enthusiastic student to join our research group. Your PhD will build upon our recent work to determine molecular mechanisms of the eukaryotic replisome. This could involve building larger replisome complexes for analysis by cryo-EM, or using the structural information we have obtained to guide sophisticated biochemical and genetic experiments using a range of cutting-edge systems that we have available in the lab. You will become an expert in protein purification and complex biochemical reconstitution, whilst also having the opportunity to gain experience in structural biology. Our group provides an excellent environment to learn new techniques, both directly from myself and from experienced post docs in the lab, whilst working on an independent project.

Funding Notes

Please see the LMB PhD website for further details: View Website

References

1. Yeeles, J.T., Deegan, T.D., Janska, A., Early, A., and Diffley, J.F. (2015). Regulated eukaryotic DNA replication origin firing with purified proteins.
Nature 519, 431-435. 


Yeeles, J.T.P., Janska, A., Early, A., and Diffley, J.F.X. (2017).
How the Eukaryotic Replisome Achieves Rapid and Efficient DNA Replication.
Mol Cell 65, 105-116.

Taylor, M.R.G., and Yeeles, J.T.P. (2018).
The Initial Response of a Eukaryotic Replisome to DNA Damage.
Mol Cell 70, 1067-1080 e1012.

Aria, V. and Yeeles, J.T.P. (2019).
Mechanism of Bidirectional Leading-Strand Synthesis Establishment at Eukaryotic DNA Replication Origins.
Mol Cell 73, 199-211 e10.


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