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


Project Description

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.

HOW TO APPLY
Applications should be made by emailing with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as 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.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to . A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Informal enquiries may be made to



Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

(2018) Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin-Resistant Mycobacterium tuberculosis. MOLECULAR CELL 72(2):263

(2017) Single-peptide DNA-dependent RNA polymerase homologous to multi-subunit RNA polymerase. NATURE COMMUNICATIONS. 8:15774

(2017) Deep sequencing approaches for the analysis of prokaryotic transcriptional boundaries and dynamics. METHODS. 120:76-84

(2017) Misincorporation by RNA polymerase is a major source of transcription pausing in vivo. NUCLEIC ACIDS RES. 45:1105-1113

(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

(2013). Mechanism of RNA polymerase III transcription termination. SCIENCE, 340: 1577-1580.

(2019) Architecture and function of the Bacillus subtillis prophage lytic cassette proteins XepA and Yoms. ACTA D (in press).

(2019) How to stabilize your protein: stability screens for thermal shift assays and nano differential scanning fluorimetry in the Virus-X project. J. VIS. EXP. (144) e58666.

(2017) New leads for Tuberculosis booster drugs by structure-based drug discovery. ORG BIOMOL CHEM. 15:10245-255.

(2017) “A tight tunable range for Ni(II) sensing and buffering in cells” NAT CHEM BIOL 13:409-414

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