Toxin-mediated degradation of mRNA during the bacterial stringent response

Bacteria adapt to stressful conditions by rapidly adjusting their metabolic rates via global regulatory responses. General mechanisms for adaption include the SOS response, general stress response, the heat-shock response and the stringent response. Factors involved in the stringent response have been identified across diverse microorganisms but their detailed molecular mechanisms of target recognition and action are still unknown. One major focus of my lab is to study how specific proteins involved in the stringent response repress translation, allowing bacteria to enter a nonreplicative latent state known as persistence.

Figure 2

The stringent response is one of the most important regulatory circuits in bacteria. The accumulation of (p)ppGpp modifies global cellular metabolism in response to changing micro-environments to optimize growth, and ultimately bacterial survival, in a very short time frame (Figure 2). Toxin-antitoxin (TA) gene pairs facilitate cell survival during the stringent response and have been implicated in biofilm formation, persistence during antibiotic treatment and bacterial pathogenesis. During times of stress such as nutritional deprivation, TA systems fine tune basic cellular processes for survival. One major function of toxin proteins is to halt protein synthesis, which conserves energy for cell survival and additionally produces truncated proteins for degradation and replenishment of the amino acid pool. Repression of translation by toxin proteins typically occurs by degradation of mRNA bound to a translating ribosome in a codon-dependent manner. This precision implies a sophisticated mechanism of RNA recognition similar to how tRNAs decode mRNA codons.

The Dunham laboratory has been studying two different ribosome-dependent toxin-antitoxin systems: Proteus vulgaris HigBA and E. coli DinJ-YafQ (Figure 3). The structures of the transrepressor complexes revealed that manner in which each toxin YafQ and HigB is repressed and furthermore that each contains distinct DNA-binding motifs implying novel repression. Future experiments aimed at determining how they specifically recognize both their RNA and DNA targets are currently ongoing.


  • Schureck MA, Maehigashi T, Miles SJ, Marquez J, Ei Cho S, Erdman R and Dunham CM. (2014) Structure of the P. vulgaris HigB-(HigA)2-HigB toxin-antitoxin complex. Journal of Biological Chemistry 289(2):1060-70. PMCID: PMC3887174. (abstract)
  • Cruz JW, Rothenbacher FP, Maehigashi T, Lane WS, Dunham CM, Woychik NA. (2014) Doc toxin is a kinase that inactivates elongation factor Tu. Journal of Biological Chemistry 289(11):7788-99. PMCID: PMC3953291. (abstract)
  • Ruangprasert A*, Maehigashi T*, Miles SJ, Giridharan N, Liu JX and Dunham CM. (2014) Mechanisms of toxin inhibition and transcriptional repression by E. coli DinJ-YafQ. Journal of Biological Chemistry 289(30):20559-69. PMCID: PMC4110269. [*These authors contributed equally]. (abstract)
  • Cruz JW, Sharp JD, Hoffer ED, Maehigashi T, Vyedenskaya IO, Konkimalla A, Husson RN, Nickels BE, Dunham CM and Woychik NA (2015). Growth-regulating Mycobacterium tuberculosis VapC-mt4 toxin is an isoacceptor-specific tRNase. Nature Communications 6:7480. PMID: 26158745. (abstract).
  • Maehigashi T*, Ruangprasert A*, Miles SJ and Dunham CM (2015). Molecular basis of ribosome regulation and mRNA hydrolysis by the E. coli YafQ toxin. Nucleic Acids Research 43(16):8002-12. PMID: 26261214. *These authors contributed equally. (abstract).
News and Views:
  • Schureck MA and Dunham CM. (2014) Bacterial warfare again targets the ribosome. Structure 22(5):661-2.  PMID: 24807074. (PMCID in process) (abstract)