Area of Interest
Bacterial responses to stress
When a bacterial pathogen infects a host, the host defends itself by producing toxic compounds and inducing unfavorable conditions for the bacterium. The bacterium in turn responds to the new environmental cues, often subverting host defenses by utilizing host-derived signals to trigger upregulation of virulence genes. We are focusing on bacterial transcription factors that respond to such host-derived signals to control expression of virulence genes. Understanding mechanisms by which bacterial pathogens change gene expression programs in response to the environmental cues associated with host infection is critical for development of antibacterial agents.
A major focus is on MarR family transcriptional regulators and the mechanism by which the binding of ligands controls their ability to regulate gene expression. For example, we are currently focusing on how such transcription factors alter gene expression programs in response to oxidative stress or changes in pH.
Organization of genomic DNA
Genomic DNA in both prokaryotes and eukaryotes is compacted to fit into cellular compartments. We are interested in architectural proteins, so named because a primary function is to induce a specific DNA topology and control DNA compaction. Architectural DNA-binding proteins play important roles in controlling processes such as DNA repair and gene expression. In eukaryotes, failure to regulate these processes correctly may lead to mutagenesis, genomic instability, and cancer.
Current goals pertain to the mechanism by which yeast HMO1 stabilizes nucleosomal arrays and the role of HMO1 in DNA repair and regulation of gene activity. Of specific interest is the role of HMO1 in coordinating gene activity in response to signaling by the Target of Rapamycin (TOR) kinase pathway, which is important for regulating cell growth in response to signals such as nutrient limitation and stress.
Gupta, A., Bedre, R., Thapa, S. S., Sabrin, A., Wang, G., Dassanayake, M. and Grove, A. Global awakening of cryptic biosynthetic gene clusters in Burkholderia thailandensis. ACS Chem. Biol. 12, 3012-3021 (2017).
Panday, A., Gupta, A., Srinivasa, K., Xiao, L., Smith, M. D. and Grove, A. DNA damage regulates direct association of TOR kinase with the RNA polymerase II-transcribed HMO1 gene. Mol. Biol. Cell. 28, 2449-2459 (2017).
Gupta, A., Fuentes, S. M. and Grove, A. Redox-sensitive MarR homologue BifR from Burkholderia thailandensis regulates biofilm formation. Biochemistry 56, 2315-2327 (2017).
Deochand, D. K., Meariman, J. K. and Grove, A. pH-dependent regulation of gene expression by Pectobacterium atrosepticum PecS. ACS Chem. Biol. 11, 2049-2056 (2016).
Panday, A. and Grove, A. The high mobility group protein HMO1 functions as a linker histone in yeast. Epigenetics Chromatin 9:13 (2016).
Sivapragasam, S. and Grove, A. Streptomyces coelicolor XdhR is a direct target of (p)ppGpp that controls expression of genes encoding xanthine dehydrogenase to promote purine salvage. Mol. Microbiol. 100, 701-718 (2016).
Grove, A. Control of RNA polymerase II-transcribed genes by direct binding of TOR kinase. Curr. Genet. 64, 131-135 (2018). Review.
Panday, A. and Grove, A. Yeast HMO1 - linker histone reinvented. Microbiol. Mol. Biol. Rev. 81:e00037-16 (2017). Review.
Deochand, D. K. and Grove, A. MarR family transcription factors: Dynamic variations on a common scaffold. Crit. Rev. Biochem. Mol. Biol. 52, 595-613 (2017). Review.