Research Interests

RNA polymerase, transcription factors, gene regulation, DNA repair, stress response, RNA sensors, bacterial resistance, bacteria-host interaction, gasotransmitters, aging mechanisms

Research Statement

Our most significant contributions to science include:

  1. Discovery and implications of RNA polymerase (RNAP) “backtracking” and “ratcheting”: In 1997 we described back-and-forth sliding of RNAP along DNA and RNA. Our group then showed that this phenomenon, which we called “backtracking”, plays the key role in regulating gene expression (via pausing and termination), in transcriptional fidelity, in genome instability, and in coupling transcription to DNA repair. We were also the first to demonstrate that RNAP is a Brownian ratchet machine. Our findings explained in mechanistical details how RNAP translocates, how it responds to regulatory signals and factors, and how it terminates transcription.
  2. Transcription coupled DNA repair (TCR). In 2014 we uncovered a general mechanism of TCR that relies on active RNAP backtracking. We found that in bacteria, UvrD binds RNAP during transcription elongation and, using its helicase activity, forces RNAP to slide backward along DNA. By inducing backtracking, UvrD exposes DNA lesions shielded by blocked RNAP, allowing the repair enzymes to gain access to sites of damage. The small molecule alarmone ppGpp and general elongation factor NusA contribute to UvrD-mediated TCR. Because backtracking is a shared feature of all cellular RNAP, this mechanism enables RNAPs to function as global DNA damage scanners in bacteria and eukaryotes.
  3. Discovery and characterization of riboswitches: In 2002 we described the first ligand-sensing mRNAs that regulate biosynthetic genes in B. subtilis. Simultaneously, Ron Breaker reported similar findings in E. coli. Since then dozens of riboswitches have been described in bacteria and eukaryotes where they control numerous genes. We have shown that riboswitches can activate and suppress gene expression acting at the level of transcription termination (both intrinsic and Rho-dependent), translation initiation, and also modulating alternative splicing and mRNA stability (in plants).
  4. Discovery of the eukaryotic RNA thermosensor and the mechanism of heat shock response: In 2006 we isolated a complex composed of the translation elongation factor eEF1A1 and a novel non-coding RNA (HSR1) that is required for activation of heat shock genes in mammals. We then showed that HSR1 serves as a bona fide molecular thermosensor, which is set for different temperatures in different organisms. We also showed that eEF1A1 orchestrates the whole process of heat shock response, from transcription activation to mRNA stabilization, transport, and translation. These findings provide a new paradigm of cellular adaptation to stress, with far-reaching clinical implications.
  5. Bacterial gasotransmitters: We have shown that endogenously produced gases NO and H2S protect bacteria from oxidative stress, immune attack, and numerous antibiotics. These results support the emerging concept of antibiotic killing, which relies on oxidative damage, and establish NO- and H2S-producing enzymes as promising new targets for antimicrobial therapy. We further showed that NO produced by bacteria inside C. elegans diffuses into animal’s tissues where it activates a defined set of genes that protect nematodes from environmental stress and extend their lifespan.

Selected Publications