Christine M. Dunham, PhD

Assistant Professor

Department of Biochemistry

Faculty member

Biochemistry, Cell and Developmental Biology Graduate Program

Faculty member

Molecular and Systems Pharmacology Graduate Program

Phone: 404-712-1756


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Research Interests

My lab is interested in determining the molecular basis for dysregulation of the bacterial ribosome resulting from different cellular environments that control bacterial proliferation and persistence. We use multidisciplinary approaches including biochemical, microbiological and structural biology techniques. Specific projects in the lab include: 1) the structural and functional basis of negative regulation of their own expression by toxin-antitoxin complexes during steady state growth, and the rapid translation of specific mRNAs to change the cellular proteome during stress conditions; 2) the role of ribosomal RNA modification enzymes that confer antibiotic resistance (in collaboration with the Conn lab).

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 replicatively inactive state known as persistence.

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 microenvironments to optimize growth, and ultimately bacterial survival, in a very short time frame. 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, bacteria turn to TA systems to fine tune basic cellular processes for survival. Type II TA complexes are small protein-protein pairs that function as transcriptional repressors of their own and, in some cases, other genes under steady state conditions. Upon activation of the stress response, cellular proteases selectively degrade antitoxin proteins, thus freeing the toxin. 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.

My lab has been studying two different ribosome-dependent toxin-antitoxin systems: Proteus vulgaris HigBA and E. coli DinJ-YafQ. 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 (Ruangprasert et al., JBC 2014 and Schureck et al., JBC 2014). Future experiments aimed at determining how they specifically recognize both their RNA and DNA targets are currently ongoing.

RNA modification and antibiotic resistance

Increasing global spread of antibiotic resistance among pathogenic bacteria threatens a post-antibiotic era in healthcare. Detailed studies of resistance mechanisms are therefore urgently required. The ribosome is a major antibiotic target, but bacteria can acquire resistance by modification of drug-binding sites. In collaboration with Prof. Graeme Conn’s lab at Emory University, we have been studying the molecular basis for antibiotic resistance arising via enzymatic modification of the small ribosomal subunit. We solved the X-ray structure of the first molecular ‘snapshot’ of 30S recognition by a human pathogen-derived, aminoglycoside-resistance rRNA methyltransferase, NpmA (Dunkle et al., PNAS 2014). Surprisingly NpmA modifies its target 16S rRNA nucleotide, A1408, by flipping the nucleotide out of its RNA helix, despite space for NpmA to access the base edge. Though it had been originally proposed that these enzymes were acquired by human and animal pathogens, they share low sequence identity with enzymes from producer bacteria such as actinomycetes. Therefore, it is an open question whether these pathogen enzymes were acquired from producers or whether they arose by convergent evolution.

Future experiments include determining how structurally dissimilar but functionally equivalent methyltransferases recognize the 30S ribosomal subunit. Our initial studies indicate that subtle differences in methyltransferase residues that direct recognition of 30S have a direct result in whether the enzyme is preloaded with its obligate SAM cofactor or whether the ribosome plays a role in recycling the reaction by-product SAH for SAM while the methyltransferase is bound to the ribosome.

Christine Dunham's Lab website