About the Project
http://www2.mrc-lmb.cam.ac.uk/groups/passmore/
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, or in the inflammatory response. 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 CPF complex that adds poly(A) tails onto mRNAs co-transcriptionally. CPF recognises specific sequences in pre-mRNAs, cleaves the pre-mRNA to define the end of the 3’ UTR, and adds a poly(A) tail of specified length. CPF also regulates transcription through its protein phosphatase activities.
We are also studying how the Ccr4-Not and Pan2-Pan3 complexes remove poly(A) tails from mRNAs in the cytoplasm. We aim to understand how these complexes are regulated, how they recognise mRNA, and the specific roles of subunits.
I am looking for a new PhD student to join our team. 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 or contact me for more information.
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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