We study the mechanism and regulation of RNA chain synthesis in bacteria using a combination of genetic, biochemical and biophysical techniques to elucidate the fine details of diverse catalytic reactions carried out by RNA polymerase, the determinants that control its translocation along the DNA template, and the molecular mechanisms by which accessory protein factors and small molecule ligands modulate RNA polymerase progression through the transcription cycle. We also investigate crosstalk between transcription and concurrent processes, such as translation, the nascent RNA folding, and DNA repair.
Bacterial virulence factor RfaH is the focal point of our current projects. RfaH belongs to the only universally conserved family of transcription factors. We showed that RfaH acts as a processivity clamp that locks around the DNA to enable RNA polymerase to transcribe long messages. Unexpectedly, our recent studies revealed that RfaH has an additional, and much larger, effect on gene expression mediated by direct recruitment of the ribosome to the nascent mRNAs that are devoid of canonical ribosome binding sites. This effect depends on unprecedented refolding of an RfaH domain from an α-helical hairpin into a β-barrel that interacts with the ribosomal protein S10. This conformational switch is similar to those that underlie protein transformation from harmless into disease-causing conformations, as in the case of prion diseases.
RfaH is also an attractive target for novel antibiotics and vaccines ‒ its target genes encode toxins, diverse virulence determinants, and conjugation functions. Inactivation of RfaH decreases urinary tract and intestinal infections and leads to more potent vaccines. Intriguingly, many antibiotic-resistance determinants isolated from clinical strains are carried on conjugative plasmids that also encode RfaH paralogs as part of their pilus synthesis operons.
Irina Artsimovitch's Curriculum Vitae [pdf]
Member, Center for RNA Biology
Recent Relevant Publications
- Artsimovitch I & Belogurov GA. (2015) Creative Math of RNA Polymerase III Termination: Sense Plus Antisense Makes More Sense. Mol Cell. 58: 974-976.
- Ruff EF, Record MT Jr & Artsimovitch I. (2015) Initial events in bacterial transcription initiation. Biomolecules. 5:1035-62.
- NandyMazumdar M & Artsimovitch I. (2015) Ubiquitous transcription factors display structural plasticity and diverse functions. Bioessays. 37, 324-34.
- Artsimovitch I. (2014) The tug of DNA repair. Nature. 505, 298-9.
- Malinen AM, Nandymazumdar M, Turtola M, Malmi H, Grocholski T, Artsimovitch I, Belogurov GA. (2014) CBR antimicrobials alter coupling between the bridge helix and the β subunit in RNA polymerase. Nat Commun. 5, 3408.
- Tomar SK & Artsimovitch I. (2013) NusG-Spt5 proteins — universal tools for transcription modification and communication. Chem Rev. 113, 8604-19.
- Tomar SK, Knauer SH, Nandy Mazumdar N, Rösch P & Artsimovitch I. (2013) Interdomain contacts control folding of transcription factor RfaH. Nucleic Acids Res. 41, 10077-85.
- 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.
- 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.
Other Relevant Publications
- 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.
- 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.
- 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, 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.
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