FAU researcher found a novel regulatory checkpoint in bacterial gene expression that may help to overcome antibiotic resistance
Cell copies parts of its DNA genome as RNA to guide the manufacturing of the proteins it needs to function normally. To respond to their environment, the cells need to tightly regulate which proteins to make, and do so primarily by controlling the RNA production. How do the cells adjust RNA production? Biophysicists at FAU Hospital and University of Oxford have found that the early stage of RNA production is a key regulatory checkpoint for gene expression in bacteria, and therefore represents new opportunities for future antibiotics development.
In bacteria, the RNA is produced by one large protein complex, RNA polymerase (RNAP). The RNAP reads the DNA sequence and builds its RNA copy by joining together nucleotides, the fundamental RNA building blocks, during a process called transcription. Because the RNA production is fundamental for the survival of bacteria, it has been massively studied and utilized as a target of antibiotics, for example those used to treat tuberculosis. However, it remained unclear whether the RNA production is also regulated at the stage of early transcription when RNAP just begun to join together the first few RNA building blocks. FAU and Oxford university researchers have joined their effort to investigate the question.
The team of researchers led by David Dulin, now at the FAU Hospital Erlangen-Nürnberg, and Achillefs N. Kapanidis at Oxford University (United Kingdom) used high-end fluorescence microscopy, which allowed to monitor individual RNAP molecules as they started to make RNA. The researchers found that initial RNA synthesis was indeed strongly regulated; a specific DNA sequence enforced the RNAP to pause for hundreds of seconds until it was able to continue the RNA production. These findings change the way early RNA synthesis in bacteria is usually portrait. “The fact that the RNAP may stay bound simultaneously to the DNA and short RNA for long time was very surprizing to us, as it contradicts the established knowledge”, says Dr. Dulin. The discovery of this new regulatory checkpoint in bacterial gene expression may represent a new target for antibiotics development. “For example, we may be able to develop compounds that lock the RNAP to the paused state and therefore kill the disease-causing bacteria”, Dr. Dulin envisions. The development of novel antibiotics has recently become a priority due to the rapid global spread of multi-drug resistant bacteria.
Further information:
Dr. David Dulin
Phone: +49-9131-85-40115
david.dulin@uk-erlangen.de