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Structure and functions of the novel type of RNA polymerases and their application in synthetic biology and biotechnology


Biosciences Institute

Prof N Zenkin , Prof Ehmke Pohl Friday, January 22, 2021 Competition Funded PhD Project (Students Worldwide)
Newcastle United Kingdom Biochemistry Evolution Genetics Microbiology Molecular Biology Structural Biology Virology

About the Project

In synthetic biology and biotechnology, there is an urgent need for alternative orthologous expression platforms for protein and RNA production and building complex synthetic networks. The existing systems based on single-subunit RNA polymerases (RNAPs) of T7 bacteriophage-type have limited capacity and applications.

Very recently we have discovered a new type of RNAPs – YONO-RNAPs (2017; Nature communications 8, 15774). These small single-subunit RNAPs are not related to any known single-subunit RNAPs, and use previously unknown mechanisms of transcription and its regulation. Being a new paradigm in the mechanisms of transcription, YONO-RNAPs may become a new much needed tool for molecular/synthetic biology and biotechnology. Our research already attracted interest from biotech companies.

The programme of work consists of fundamental and translational aims: to determine the mechanisms of transcription and the structure of this new type of RNAPs, understand their roles in their bacteriophage/bacterial hosts, and to develop YONO-RNAPs-based orthologous gene expression systems.

The proposed work will have potential impacts in molecular biology, evolution, biotechnology and health: (i) Biochemical and structural characterisation of YONO-RNAPs promises discovery of novel mechanisms of transcription and its regulation. (ii) The work promises delivery of much needed new molecular tools for molecular/synthetic biology and biotechnology applications. (iii) YONO-RNAPs are encoded by completely unexplored bacteriophages of many clinically, industrially and agriculturally important bacteria (various Bacilli, Clostridia, cyanobacteria); the proposed research will provide information about biology of these bacteriophages, which may help intelligent manipulation of their important bacterial hosts.

The project offers training in a wide range of molecular biology, genetics and structural biology techniques as well as novel methods based on next generation sequencing and accompanying bioinformatics tools (see for example our papers: Molecular Cell (2018) 72:263; Nature Communications (2017) 8:15774; Science (2013) 340:1577). The project will be based in the Centre for Bacterial Cell Biology of Newcastle University, which brings together leading scientists in the field of biology of bacterial cell. The Centre is situated in the new building fitted with the state of the art equipment, and provides unique scientific environment. 

Informal enquiries may be made to

HOW TO APPLY

Applications should be made by emailing with a CV and a covering letter, including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project/s and at the selected University. Applications not meeting these criteria will be rejected. We will also require electronic copies of your degree certificates and transcripts.

In addition to the CV and covering letter, please email a completed copy of the Application Details Form (Word document) to , noting the additional details that are required for your application which are listed in this form. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.


Funding Notes

Studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

1. Stevenson-Jones F., Woodgate J., Castro-Roa D, Zenkin N*. (2020) Ribosome reactivates transcription by physically pushing RNA polymerase out of transcription arrest. Proc Natl Acad Sci U S A. pii: 201919985. doi: 10.1073/pnas.1919985117
2. Mosaei H., Molodtsov, V., Kepplinger B., Harbottle J., Moon C., Jeeves R., Ceccaroni L., Shin, Y., Morton-Laing S., Marrs M., Wills C., Clegg W., Yuzenkova Y., Perry J., Bacon J., Errington J., Allenby N., Hall M., Murakami K., Zenkin N*.(2018) Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin-Resistant Mycobacterium tuberculosis. Molecular Cell 72(2):263 doi: 10.1016/j.molcel.2018.08.028
3. Forrest, D., James, K., Yuzenkova, Y., Zenkin, N*. (2017) Single-peptide DNA-dependent RNA polymerase homologous to multi-subunit RNA polymerase. Nature Communications. 8:15774. doi: 10.1038/ncomms15774.
4. James, K., Gamba, P., Cockell, S.J., Zenkin, N*. (2017) Misincorporation by RNA polymerase is a major source of transcription pausing in vivo. Nucleic Acids Res.
45:1105-1113. doi: 10.1093/nar/gkw969.
5. van Nues, R. W., Castro-Roa, D., Yuzenkova, Y., Zenkin, N*.(2016) Ribonucleoprotein particles of bacterial small non-coding RNA IsrA (IS61 or McaS) and its interaction with RNA polymerase core may link transcription to mRNA fate. Nucleic Acids Res, 44(6):2577-92 doi:10.1093/nar/gkv1302.
6. Castro-Roa, D., Garcia-Pino, A., van Nuland, N. A. J., Loris, R., and Zenkin, N*. (2013) The Fic protein Doc uses an inverted substrate to phosphorylate and inactivate EF-Tu. Nat Chem Biol 9:811-7
7. Germain, E., Castro-Roa, D., Zenkin, N*., and Gerdes, K. (2013) Molecular Mechanism of Bacterial Persistence by HipA. Molecular Cell 52:248-54
8. Nielsen, S.U., Yuzenkova, Y., and Zenkin, N*. (2013). Mechanism of RNA polymerase III transcription termination Science, 340: 1577-1580.
9. Bochkareva, A., Yuzenkova, Y., Tadigotla, V. and Zenkin, N*. (2012). Factor-independent transcription pausing caused by recognition of the RNA-DNA hybrid sequence. EMBO J 31, 630-639
10. Yuzenkova, Y., Tadigotla, V.R., Severinov, K., and Zenkin, N*. (2011). A new basal promoter element recognized by RNA polymerase core enzyme. EMBO J 30, 3766-3775.
11. Yuzenkova, Y., Zenkin, N*. (2010) Central role of the RNA polymerase trigger loop in intrinsic RNA hydrolysis Proc Natl Acad Sci U S A 107(24):10878-83
12. Zenkin, N*., Yuzenkova, Y. and Severinov, K. (2006) Transcript-assisted transcriptional proofreading. Science, 313, 518-20.
13. Zenkin, N*., Naryshkina, T., Kuznedelov, K. and Severinov, K. (2006) The mechanism of DNA primer synthesis by RNA polymerase. Nature, 439, 617


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