Centre for Synthetic Biology and the Bioeconomy

Staff Profile

Professor Nikolay Zenkin

Professor of Molecular Biology

Research

Molecular basis of gene expression

Transcription, copying genetic information into RNA, is the first step of gene expression. In all living organisms transcription is accomplished by conserved multi-subunit RNA polymerases, one of the most ancient enzymes on the planet. Understanding functions of RNA polymerase are essential for understanding evolution of Life of the planet. Importantly, malfunctions of RNA polymerases are linked to various human diseases including cancer and Alzheimer. Also transcription is the potent target for antimicrobials. Many mechanistic details of the functioning of RNA polymerases are not clear. Furthermore RNA polymerases are imbedded in intricate relations with other cellular machineries, such as translation in prokaryotes or replication and repair in all organisms. Regulation of these interactions is pivotal for coordination of cellular processes, correct gene expression and ultimately for survival of organisms. The mechanisms underlining these interactions and their regulation are also poorly understood.

We are investigating transcription. All possible aspects: from mechanisms of reactions and inhibition by antibiotics to regulation and interactions with other cellular machineries, such as translation, splicing and replication. We use classical biochemistry and molecular biology, structural biology, some unique experimental systems as well as novel techniques. In vitro we investigate bacterial and archaeal RNA polymerases as well as eukaryotic RNA polymerases I, II and III. In vivo we are focusing on bacterial transcription.

The main goal of our study is to understand how RNA polymerase evolved to the enzyme we know today, and how it functions and is regulated in the modern cells. Another important aspect of our work is to look for the ways of manipulation of RNA polymerases (such as specific inhibition) in order to control pathogenicity.

Bacterial toxin-antitoxin systems

Bacteria invented several mechanisms to fight against their enemies –bacteriophages and antibiotics. One of such systems, toxin-antitoxin (TA) systems, involves a large number of small proteins, called toxins, which reversibly target essential processes in the bacterial cell to stop these processes and bring the cell to dormancy. Such dormant cells become temporarily resistant to antibiotics (phenomenon called persistence) because antibiotic targets are temporarily non-functional in them, as well as become “not interesting” to bacteriophages, because they cannot propagate in dormant cells. There are also some other biological important phenomena, such as programmed cell death and addiction to plasmids, linked to TA systems. TA systems involve large number of activities and targets, many of which are not yet known or characterised.

We are interested in mechanistic and catalytic details of functioning of TAs and the outcomes of their action for their targets.

 

Interests:

Specific: cellular machineries working with nucleic acids.

General: molecular evolution, physics of high gravities and velocities.


Selected publications:

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 72:263

 

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.

 

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

 

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 44:2577

 

Castro-Roa, D., Garcia-Pino, A., De Gieter, S., 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. NATURE CHEM BIOL 9:811-7

 

Germain, E., Daniel Castro-Roa, D., Zenkin, N.*. and Gerdes, K. (2013) Molecular Mechanism of Bacterial Persistence by HipA. MOLECULAR CELL 52:248-54

 

Yuzenkova, Y., Roghanian, M., Bochkareva, A., Zenkin, N.* (2013) Tagetitoxin inhibits transcription by stabilizing pre-translocated state of the elongation complex. NUCLEIC ACIDS RES, 41:9257-65

 

Nielsen, S.U., Yuzenkova, Y., and Zenkin, N*. (2013). Mechanism of RNA polymerase III transcription termination. SCIENCE 340:1577-1580

 

Zenkin, N*. (2012). Hypothesis: emergence of translation as a result of RNA helicase evolution. J MOL EVOL 74:249-256

 

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

 

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

 

Yuzenkova Y., Zenkin N*. (2010)  Central role of the RNA polymerase trigger loop in intrinsic RNA hydrolysis PROC NATL ACAD SCI U S A 107:10878-83

 

Zenkin, N*., Yuzenkova, Y. and Severinov, K. (2006) Transcript-assisted transcriptional proofreading. SCIENCE, 313:518-20.

 

Zenkin, N*., Naryshkina, T., Kuznedelov, K. and Severinov, K. (2006) The mechanism of DNA primer synthesis by RNA polymerase. NATURE, 439:617

 

Temiakov, D., Zenkin, N. (equal contr.), Vassylyeva, M. N., Perederina, A., Tahirov, T. H., Kashkina, E., Savkina, M., Zorov, S., Nikiforov, V., Igarashi, N., Matsugaki, N., Wakatsuki, S., Severinov, K. and Vassylyev, D. G. (2005). Structural basis of transcription inhibition by antibiotic streptolydigin. MOLECULAR CELL 19:655-66.

 

Publications