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Mechanisms of molecular machines

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

Project Description


Gene expression is tightly controlled to allow rapid responses to cellular stimuli. It is regulated through transcription, translation and mRNA stability. Its deregulation is associated with human diseases (e.g. cancer).

Poly(A) tails are found on almost all eukaryotic mRNAs. They play important roles in mRNA stability, are required for export of mRNA from the nucleus and regulate the efficiency of translation. Thus, control of poly(A) tail length can be used to fine-tune protein synthesis, for example during development. Although the proteins that add and remove poly(A) tails are known, their mechanisms are poorly understood.

We aim to understand how macromolecular machines contribute to the regulation of gene expression. Specifically, we are investigating the multi-protein complexes that add or remove poly(A) tails on mRNAs. We aim to understand how these complexes are regulated, how they recognise mRNA, and the specific roles of subunits.

I am looking for a motivated and enthusiastic student to join the group. A wide range of techniques are employed by the group, including cryo-electron microscopy (cryo-EM), x-ray crystallography, genetics, biophysics and biochemical assays.

Please see my website for more information.

Funding Notes

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

References


Casañal A, Kumar A, Hill CH, Easter AD, Emsley P, Degliesposti G, Gordiyenko Y, Santhanam B, Wolf J, Wiederhold K, Dornan GL, Skehel M, Robinson CV and Passmore LA (2017) Architecture of eukaryotic mRNA 3′-end processing machinery Science 348: 1056-1059

Webster MW, Chen YH, Stowell JAW, Alhusaini N, Sweet T, Graveley BR, Coller J, Passmore LA (2018) mRNA Deadenylation Is Coupled to Translation Rates by the Differential Activities of Ccr4-Not Nucleases. Mol Cell 70(6):1089-1100.

Tang TTL, Stowell JAW, Hill CH, Passmore LA “The intrinsic structure of poly(A) RNA determines the specificity of Pan2 and Caf1 deadenylases” (2019) Nature Struct Mol Biol 26: 433-442

Hill CH, Boreikaitė V, Kumar A, Casañal A, Kubík P, Degliesposti G, Maslen S, Mariani A, von Loeffelholz O, Girbig M, Skehel M, Passmore LA “Activation of the endonuclease that defines mRNA 3ʹ-ends requires incorporation into an 8-subunit core cleavage and polyadenylation factor complex” (2019) Mol Cell 73, 1217–1231

Webster MW, Stowell JAW, Passmore LA “The mechanism of Ccr4-Not recruitment to specific mRNAs involves sequence-selective tethering by RNA-binding proteins” (2019) eLife 8:e40670 doi: 10.7554/eLife.40670


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