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POLYAMACHINES SIGNED

The polyA machinery: Elucidating the molecular mechanisms of mRNA polyadenylation, deadenylation and RNA recognition

Total Cost €

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EC-Contrib. €

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Partnership

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Project "POLYAMACHINES" data sheet

The following table provides information about the project.

Coordinator
UNITED KINGDOM RESEARCH AND INNOVATION 

There are not information about this coordinator. Please contact Fabio for more information, thanks.

 Coordinator Country United Kingdom [UK]
 Total cost 2˙016˙697 €
 EC max contribution 2˙016˙697 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2016-COG
 Funding Scheme ERC-COG
 Starting year 2017
 Duration (year-month-day) from 2017-04-01   to  2022-03-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    UNITED KINGDOM RESEARCH AND INNOVATION UK (SWINDON) coordinator 2˙016˙697.00
2    MEDICAL RESEARCH COUNCIL UK (SWINDON) coordinator 0.00

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 Project objective

Gene expression is tightly regulated to allow rapid responses to cellular stimuli. In eukaryotes, the 3´ polyA tail of mRNAs plays key roles in post-transcriptional control. The Cleavage and Polyadenylation Factor (CPF), Ccr4–Not and Pan2–Pan3 multiprotein complexes add or remove polyA tails to regulate mRNA stability and efficiency of translation. They control expression of genes in the inflammatory response, miRNA-targeted gene silencing and expression of maternal mRNAs in oocyte development. These processes are deregulated in disease, including cancer and neurological disorders.

Although the proteins that add and remove polyA tails are known, their mechanisms are poorly understood. My lab recently established methods to reconstitute the polyA machinery. This led to new insights into the link between transcription and polyadenylation, new understanding of the molecular mechanisms of deadenylation, and details of RNA recruitment.

In this proposal, my objective is to understand the molecular basis for polyadenylation and deadenylation of specific mRNAs. This is now possible because of our novel methodological and biological advances. We will determine high-resolution structures of the polyA machinery using electron cryo-microscopy (cryo-EM), reconstitute their biochemical activities in vitro and study their in vivo functional roles. We use this integrated approach to study intact multiprotein complexes, not individual subunits or domains. This involves considerable technical challenges and an investment in developing high quality purifications and new structural methods. I will determine how the four enzymatic activities of CPF are coupled, the mechanisms by which Ccr4–Not targets specific RNAs, and the molecular basis for RNA recognition by Pan2–Pan3. Together, this will provide new biological and technological insights, leading to understanding of fundamental processes in gene expression and the role of polyA tails in disease.

 Publications

year authors and title journal last update
List of publications.
2019 Michael W Webster, James AW Stowell, Lori A Passmore
RNA-binding proteins distinguish between similar sequence motifs to promote targeted deadenylation by Ccr4-Not
published pages: , ISSN: 2050-084X, DOI: 10.7554/elife.40670
eLife 8 2019-11-26
2019 Chris H. Hill, Vytautė Boreikaitė, Ananthanarayanan Kumar, Ana Casañal, Peter Kubík, Gianluca Degliesposti, Sarah Maslen, Angelica Mariani, Ottilie von Loeffelholz, Mathias Girbig, Mark Skehel, Lori A. Passmore
Activation of the Endonuclease that Defines mRNA 3′ Ends Requires Incorporation into an 8-Subunit Core Cleavage and Polyadenylation Factor Complex
published pages: 1217-1231.e11, ISSN: 1097-2765, DOI: 10.1016/j.molcel.2018.12.023
Molecular Cell 73/6 2019-11-26
2019 Terence T. L. Tang, James A. W. Stowell, Chris H. Hill, Lori A. Passmore
The intrinsic structure of poly(A) RNA determines the specificity of Pan2 and Caf1 deadenylases
published pages: 433-442, ISSN: 1545-9993, DOI: 10.1038/s41594-019-0227-9
Nature Structural & Molecular Biology 26/6 2019-11-26
2018 Michael Lidschreiber, Ashley D Easter, Sofia Battaglia, Juan B Rodríguez-Molina, Ana Casañal, Manuel Carminati, Carlo Baejen, Pawel Grzechnik, Kerstin C Maier, Patrick Cramer, Lori A Passmore
The APT complex is involved in non-coding RNA transcription and is distinct from CPF
published pages: , ISSN: 0305-1048, DOI: 10.1093/nar/gky845
Nucleic Acids Research 2019-11-26
2017 Michael W. Webster, James A.W. Stowell, Terence T.L. Tang, Lori A. Passmore
Analysis of mRNA deadenylation by multi-protein complexes
published pages: 95-104, ISSN: 1046-2023, DOI: 10.1016/j.ymeth.2017.06.009
Methods 126 2019-04-18
2017 Ana Casañal, Ananthanarayanan Kumar, Chris H. Hill, Ashley D. Easter, Paul Emsley, Gianluca Degliesposti, Yuliya Gordiyenko, Balaji Santhanam, Jana Wolf, Katrin Wiederhold, Gillian L. Dornan, Mark Skehel, Carol V. Robinson, Lori A. Passmore
Architecture of eukaryotic mRNA 3′-end processing machinery
published pages: 1056-1059, ISSN: 0036-8075, DOI: 10.1126/science.aao6535
Science 358/6366 2019-04-18
2018 Michael W. Webster, Ying-Hsin Chen, James A.W. Stowell, Najwa Alhusaini, Thomas Sweet, Brenton R. Graveley, Jeff Coller, Lori A. Passmore
mRNA Deadenylation Is Coupled to Translation Rates by the Differential Activities of Ccr4-Not Nucleases
published pages: 1089-1100.e8, ISSN: 1097-2765, DOI: 10.1016/j.molcel.2018.05.033
Molecular Cell 70/6 2019-04-18

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