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Mechanisms of Transcription Proofreading

Objective

Transcription, the copying of DNA into RNA, is the first step in the realisation of genetic information. RNA is either directly used by the cell or decoded into proteins during translation. The accuracy of transcription is thus essential for proper functioning of the cell. In all living organisms transcription is performed by multisubunit RNA polymerases, enzymes that are highly conserved in evolution from bacteria to humans. Surprisingly, the mechanisms that ensure accuracy of transcription remain largely unknown. Recently I discovered a novel mechanism of transcriptional proofreading used by bacterial RNA polymerase. I showed that the RNA transcript itself assists RNA polymerase in identifying and correcting mistakes. This discovery led to the hypothesis that this transcript-assisted proofreading is the universal mechanism of transcriptional error correction in all three domains of life. In this proposal we will investigate this hypothesis and search for other mechanisms of transcriptional proofreading used by bacterial, archaeal, and three eukaryotic RNA polymerases. For the first time experimental systems will be built for the simultaneous investigation of transcription elongation complexes formed by bacterial, archaeal and eukaryotic RNA polymerases I, II and III, which will be used to elucidate the mechanisms of error correction used by these RNA polymerases. Using molecular modelling, directed mutagenesis and in vivo screenings we will investigate the impact of these proofreading mechanisms on the total fidelity of transcription in vitro and in vivo. Experimental systems built in this research may be of use for screening of potential antibacterial and antifungal drugs taking advantage of the simultaneous investigation of RNA polymerases from all domains of Life. This research may also have potential applications in drug design by providing new targets for antibiotics.

Field of science

  • /natural sciences/biological sciences/microbiology/bacteriology
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes

Call for proposal

ERC-2007-StG
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

UNIVERSITY OF NEWCASTLE UPON TYNE
Address
Kings Gate
NE1 7RU Newcastle Upon Tyne
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 149 831
Principal investigator
Nikolay Zenkin (Dr)
Administrative Contact
Amanda Gregory (Dr.)

Beneficiaries (1)

UNIVERSITY OF NEWCASTLE UPON TYNE
United Kingdom
EU contribution
€ 1 149 831
Address
Kings Gate
NE1 7RU Newcastle Upon Tyne
Activity type
Higher or Secondary Education Establishments
Principal investigator
Nikolay Zenkin (Dr)
Administrative Contact
Amanda Gregory (Dr.)