M.S. Moscow State Univ., 1990
Ph.D. Univ. of Tennessee, 1996
Postdoc. Univ. of Wisconsin, 1996-2001
The focal point of the research in our lab is RNA polymerase (RNAP), the enzyme that is responsible for the first step in gene expression, mRNA synthesis. RNAP accomplishes this task during the transcription cycle that is composed of three major steps: initiation, elongation, and termination. All these steps are subject to elaborate control by numerous regulatory proteins and small effectors. RNAP is also an attractive target for antibacterial drugs. We are currently focusing on four projects:
Mechanism and regulation of RNA chain elongation and termination
The rate of transcription is determined by the nucleic acid signals that serve as regulatory checkpoints at which RNAP could be modified by action of auxiliary factors, and therefore determine the gene expression patterns in all organisms. Certain DNA and RNA sequences trigger RNAP isomerization into off-pathway states, which may either temporarily halt or terminate RNA synthesis. We study how RNAP itself recognizes transcription roadblocks and how auxiliary factors affect its behavior.
RfaH, an elongation enhancer and a virulence factor
RfaH is required for the expression of long operons encoding toxins, antibiotics, capsules, and F-pili, all of which are molecules that contribute to pathogenesis. RfaH activates expression of these genes during both transcription and translation. As a transcription factor, RfaH "switches" RNAP into a state that ignores termination signals. As a translation factor, RfaH interacts with the ribosome to recruit it to poorly translated mRNAs. RfaH transformation into a translation factor requires a complete refolding of its C-terminal domain. We are studying RfaH roles in coupling of transcription, translation and secretion, and the mechanism of its unique refolding.
Molecular mechanisms of the RNAP inhibitors
Inhibitors of bacterial RNAP are used as antibiotics to treat bacterial infections and in research to gain insights into molecular mechanisms that regulate transcription. We are working on the mechanism of RNAP inhibition by streptolydigin, rifamycins, tagetitoxin, CBRs, myxopyronin, etc. We perform detailed analysis of the mechanism of action of these inhibitors by a combination of genetic and biochemical techniques.
Regulation of RNAP response to stress and starvation
In bacteria, amino acid starvation triggers the stringent response during which the ribosomal RNA operons are repressed whereas the genes for the synthesis and transport of amino acids are activated to restore the balance between the ribosome production and the amino acid pools. In E. coli, the stringent response is mediated by alarmone ppGpp (a.k.a. the “magic spot”) and its accessory protein DksA. Both factors directly bind to RNAP and alter the pathway of initiation complex formation. We aim to elucidate the molecular mechanism of the ppGpp/DksA joint action. We also plan to characterize DksA-like proteins in pathogens that contain several DksA paralogs. We propose that these paralogs mediate adaptation to diverse stresses including those that bacteria encounter upon entry into their hosts.
- Burmann BM, Knauer SH, Sevostyanova A, Schweimer K, Mooney RA, Landick R, Artsimovitch I & Rösch P. (2012) An α-helix to β-barrel domain switch transforms the transcription factor RfaH into a translation factor. Cell, 150, 291-303.
- Deaconescu AM, Sevostyanova A, Artsimovitch I & Grigorieff N. (2012) NER machinery recruitment by the transcription-repair coupling factor involves unmasking of a conserved intramolecular interface. Proc Natl Acad Sci U S A. 109, 3353-8.
- Perdrizet GA II, Artsimovitch I, Furman R, Sosnick TR & Pan T. (2012) Transcriptional pausing coordinates folding of the aptamer domain and the expression platform of a riboswitch. Proc Natl Acad Sci U S A. 109, 3323-8.
- Furman R, Sevostyanova A & Artsimovitch I. (2011) Transcription initiation factor DksA has diverse effects on RNA chain elongation. Nucleic Acids Res. 40, 3392-402.
- Artsimovitch I, Svetlov V, Nemetski SM, Epshtein V, Cardozo T & Nudler E. (2011) Tagetitoxin inhibits RNA polymerase through trapping of the trigger loop. J Biol Chem. 286, 40395-400.
- Sevostyanova A, Belogurov GA, Mooney RA, Landick R & Artsimovitch I. (2011) The beta subunit gate loop is required for RNA polymerase modification by RfaH and NusG. Mol Cell. 43, 253-62.
- Santangelo TJ & Artsimovitch I. (2011) Termination and antitermination: RNA polymerase runs a stop sign. Nat Rev Microbiol. 9, 319-29.
- Blaby-Haas CE, Furman R, Rodionov DA, Artsimovitch I & de Crécy-Lagard V. (2011) Role of a Zn-independent DksA in Zn homeostasis and stringent response. Mol Microbiol. 79, 700-15.
OTHER RELEVANT PUBLICATIONS
- Belogurov GA, Vassylyeva MN, Sevostyanova A, Appleman JR, Xiang AX, Lira R, Webber SE, Klyuyev S, Nudler E, Artsimovitch I & Vassylyev DG. (2009) Transcription inactivation through local refolding of the RNA polymerase structure. Nature. 457, 332-5.
- Belogurov GA, Mooney RA, Svetlov V, Landick R & Artsimovitch I. (2009) Functional specialization of transcription elongation factors. EMBO J. 28, 112-22.
- Sevostyanova A, Svetlov V, Vassylyev DG & Artsimovitch I. (2008) The elongation factor RfaH and the initiation factor sigma bind to the same site on the transcription elongation complex. Proc Natl Acad Sci U S A. 105, 865-70.
- Vassylyev DG, Vassylyeva MN, Zhang J, Palangat M, Artsimovitch, I & Landick R. (2007) Structural basis for substrate loading in bacterial RNA polymerase. Nature. 448, 163-8.
- Vassylyev DG, Vassylyeva MN, Perederina A, Tahirov TH & Artsimovitch, I. (2007) Structural basis for transcription elongation by bacterial RNA polymerase. Nature. 448, 157-62.
- Belogurov GA, Vassylyeva MN, Svetlov V, Klyuyev S, Grishin NV, Vassylyev DG & Artsimovitch I. (2007) Structural basis for converting a general transcription factor into an operon-specific virulence regulator. Mol Cell. 26, 117-29.
- Vassylyev DG, Svetlov V, Vassylyeva MN, Perederina A, Igarashi N, Matsugaki N, Wakatsuki S & Artsimovitch I. (2005) Structural basis for transcription inhibition by tagetitoxin. Nat Struct Mol Biol. 12, 1086-93.
- Artsimovitch I, Vassylyeva MN, Svetlov D, Svetlov V, Perederina A, Igarashi N, Matsugaki N, Wakatsuki S, Tahirov, TH & Vassylyev DG. (2005) Allosteric modulation of the RNA polymerase catalytic reaction is an essential component of transcription control by rifamycins. Cell. 122, 351-63.
- Perederina A, Svetlov V, Vassylyeva MN, Tahirov TH, Yokoyama S, Artsimovitch I & Vassylyev DG. (2004) Regulation through the secondary channel--structural framework for ppGpp-DksA synergism during transcription. Cell. 118, 297-309.
- Artsimovitch I, Chu C, Lynch AS & Landick R. (2003) A new class of bacterial RNA polymerase inhibitor affects nucleotide addition. Science. 302, 650-4.
The all-time favorite:
- Artsimovitch I & Landick R. (2000) Pausing by bacterial RNA polymerase is mediated by mechanistically distinct classes of signals. Proc Natl Acad Sci U S A. 97, 7090-5.