Robustness and evolvability in natural chemical resistance: identification of novel systems properties, biochemical mechanisms and regulatory interactions

Venancio, Thiago M.; Balaji, S.; Geetha, S.; Aravind, L.

doi:10.1039/c002567b

Cited by 12 publications

(51 citation statements)

References 133 publications

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“…We also excluded strains where soraphen A sensitivity was potentially linked to a general inhibition of lipid metabolism. We took advantage of a previously published chemical-phenotype network (CP network), which is a bipartite hybrid network comprising 426 chemicals and 5233 ORFs whose deletion leads to sensitivity to those compounds [15]. Using these data, we constructed a subnetwork, the Lipid Chemical Phenotype (LipCP) network (S3 Table), consisting only of drugs that are known to affect lipid metabolism (e.g.…”

Section: Resultsmentioning

confidence: 99%

A Chemogenomic Screen Reveals Novel Snf1p/AMPK Independent Regulators of Acetyl-CoA Carboxylase

Bozaquel-Morais¹,

Madeira²,

Venâncio³

et al. 2017

PLoS ONE

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Acetyl-CoA carboxylase (Acc1p) is a key enzyme in fatty acid biosynthesis and is essential for cell viability. To discover new regulators of its activity, we screened a Saccharomyces cerevisiae deletion library for increased sensitivity to soraphen A, a potent Acc1p inhibitor. The hits identified in the screen (118 hits) were filtered using a chemical-phenotype map to exclude those associated with pleiotropic drug resistance. This enabled the identification of 82 ORFs that are genetic interactors of Acc1p. The main functional clusters represented by these hits were “transcriptional regulation”, “protein post-translational modifications” and “lipid metabolism”. Further investigation of the “transcriptional regulation” cluster revealed that soraphen A sensitivity is poorly correlated with ACC1 transcript levels. We also studied the three top unknown ORFs that affected soraphen A sensitivity: SOR1 (YDL129W), SOR2 (YIL092W) and SOR3 (YJR039W). Since the C18/C16 ratio of lipid acyl lengths reflects Acc1p activity levels, we evaluated this ratio in the three mutants. Deletion of SOR2 and SOR3 led to reduced acyl lengths, suggesting that Acc1p is indeed down-regulated in these strains. Also, these mutants showed no differences in Snf1p/AMPK activation status and deletion of SNF1 in these backgrounds did not revert soraphen A sensitivity completely. Furthermore, plasmid maintenance was reduced in sor2Δ strain and this trait was shared with 18 other soraphen A sensitive hits. In summary, our screen uncovered novel Acc1p Snf1p/AMPK-independent regulators.

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Section: Resultsmentioning

confidence: 99%

A Chemogenomic Screen Reveals Novel Snf1p/AMPK Independent Regulators of Acetyl-CoA Carboxylase

Bozaquel-Morais¹,

Madeira²,

Venâncio³

et al. 2017

PLoS ONE

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“…Our analysis based on comparative genomics and sequence-structure comparisons detailed in this study suggests that the ter components and TelA are at the center of a rather extensive system of interacting proteins and small-molecules whose “tentacles” extend to a wide range of biological processes. Thus, in a sense the ter components and TelA appear to resemble the complexes that have been uncovered via chemogenomics studies in eukaryotes that provide robustness to the system against a diverse array of mechanistically distinct chemical stresses 2 .…”

Section: A Synthetic Overview and General Conclusionmentioning

confidence: 97%

“…These studies have revealed that organisms have multiple complementary approaches to deal with chemical stress, which together confer both robustness and evolvability to cellular systems 2, 9 . They have also indicated that responses to the same substances might be channelized via distinct pathways – some of these are generic pathways that facilitate countering of diverse deleterious substances irrespective of their structure and mode of action 3 .…”

Section: Introductionmentioning

confidence: 99%

“…They have also indicated that responses to the same substances might be channelized via distinct pathways – some of these are generic pathways that facilitate countering of diverse deleterious substances irrespective of their structure and mode of action 3 . These include both general efflux mechanisms such as those constituted by multi-drug resistance proteins (MDRs) as well as back-ups for various cellular systems that reinforce them against the action of chemicals, or function analogous to phenotypic capacitors by allowing the cell to withstand attacks on multiple nodes in the biological networks 2, 3, 6, 7, 9 . Other pathways are more specific and are deployed against particular substances or classes of substances and potentially neutralize them by acting on them directly 2, 6 .…”

Section: Introductionmentioning

confidence: 99%

“…These include both general efflux mechanisms such as those constituted by multi-drug resistance proteins (MDRs) as well as back-ups for various cellular systems that reinforce them against the action of chemicals, or function analogous to phenotypic capacitors by allowing the cell to withstand attacks on multiple nodes in the biological networks 2, 3, 6, 7, 9 . Other pathways are more specific and are deployed against particular substances or classes of substances and potentially neutralize them by acting on them directly 2, 6 . Furthermore, stress response might involve systems acting at various levels of cellular organization and compartmentalization 3, 5, 7 .…”

Section: Introductionmentioning

confidence: 99%

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Ter-dependent stress response systems: novel pathways related to metal sensing, production of a nucleoside-like metabolite, and DNA-processing

2012

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The mode of action of the bacterial ter cluster and TelA genes, implicated in natural resistance to tellurite and other xenobiotic toxic compounds, pore-forming colicins and several bacteriophages has remained enigmatic for almost two decades. Using comparative genomics, sequence-profile searches and structural analysis we present evidence that the ter gene products and their functional partners constitute previously underappreciated, chemical stress response and anti-viral defense systems of bacteria. Based on contextual information from conserved gene neighborhoods and domain architectures, we show that the ter gene products and TelA lie at the center of membrane-linked metal recognition complexes with regulatory ramifications encompassing phosphorylation-dependent signal transduction, RNA-dependent regulation, biosynthesis of nucleoside-like metabolites and DNA processing. Our analysis suggests that the multiple metal-binding and non-binding TerD paralogs and TerC are likely to constitute a membrane-associated complex, which might also include TerB and TerY, and feature several, distinct metal-binding sites. Versions of the TerB domain might also bind small molecule ligands and link the TerD paralog-TerC complex to biosynthetic modules comprised of phosphoribosyltransferases (PRTases), ATP grasp amidoligases, TIM-barrel carbon-carbon lyases, and HAD phosphoesterases, which are predicted to synthesize novel nucleoside-like molecules. One of the PRTases is also likely to interact with RNA by means of its Pelota/Ribosomal protein L7AE-like domain. The von Willebrand factor A domain protein, TerY, is predicted to be part of a distinct phosphorylation switch, coupling a protein kinase and a PP2C phosphatase. We show, based on the evidence from numerous conserved gene neighborhoods and domain architectures, that both the TerB and TelA domains have been linked to diverse lipid-interaction domains, such as two novel PH-like and the Coq4 domains, in different bacteria and are likely to comprise membrane-associated sensory complexes that might additionally contain periplasmic binding-protein-II and OmpA domains. The TerD and TerB domains and the TerY-associated phosphorylation system are also functionally linked to distinct DNA-processing complexes, which contain proteins with SWI2/SNF2 and RecQ-like helicases, multiple AAA+ ATPases, McrC-N-terminal domain proteins, several restriction endonuclease fold DNases, DNA-binding domains and a type-VII/Esx-like system, which is at the center of a predicted DNA transfer apparatus. These DNA-processing modules and associated genes are predicted to be involved in restriction or suicidal action in response to phages and possibly repairing xenobiotic-induced DNA damage. In some eukaryotes, certain components of the ter system appear to have recruited to function in conjunction with the ubiquitin system and calcium-signaling pathways.

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Diversity and evolution of chromatin proteins encoded by DNA viruses

Souza

Iyer

Aravind

2010

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Double-stranded DNA viruses display a great variety of proteins that interact with host chromatin. Using the wealth of available genomic and functional information, we have systematically surveyed chromatin-related proteins encoded by dsDNA viruses. The distribution of viral chromatin-related proteins is primarily influenced by viral genome size and the superkingdom to which the host of the virus belongs. Smaller viruses usually encode multifunctional proteins that mediate several distinct interactions with host chromatin proteins and viral or host DNA. Larger viruses additionally encode several enzymes, which catalyze manipulations of chromosome structure, chromatin remodeling and covalent modifications of proteins and DNA. Among these viruses, it is also common to encounter transcription factors and DNA-packaging proteins such as histones and IHF/HU derived from cellular genomes, which might play a role in constituting virus-specific chromatin states. Through all size ranges a subset of domains in viral chromatin proteins appear to have been derived from those found in host proteins. Examples include the Zn-finger domains of the E6 and E7 proteins of papillomaviruses, SET-domain methyltransferases and Jumonji-related demethylases in certain nucleocytoplasmic large DNA viruses and BEN domains in poxviruses and polydnaviruses. In other cases, chromatin-interacting modules, such as the LxCxE motif, appear to have been widely disseminated across distinct viral lineages, resulting in similar retinoblastoma targeting strategies. Viruses, especially those with large linear genomes, have evolved a number of mechanisms to manipulate viral chromosomes in the process of replication-associated recombination. These include topoisomerases, Rad50/SbcC-like ABC ATPases and a novel recombinase system in bacteriophages utilizing RecA and Rad52 homologs. Larger DNA viruses also encode SWI2/SNF2 and A18-like ATPases which appear to play specialized roles in transcription and recombination. Finally, it also appears that certain domains of viral provenance have given rise to key functions in eukaryotic chromatin such as a HEH domain of chromosome tethering proteins and the TET/JBP-like cytosine and thymine hydroxylases.

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Robustness and evolvability in natural chemical resistance: identification of novel systems properties, biochemical mechanisms and regulatory interactions

Cited by 12 publications

References 133 publications

A Chemogenomic Screen Reveals Novel Snf1p/AMPK Independent Regulators of Acetyl-CoA Carboxylase

A Chemogenomic Screen Reveals Novel Snf1p/AMPK Independent Regulators of Acetyl-CoA Carboxylase

Ter-dependent stress response systems: novel pathways related to metal sensing, production of a nucleoside-like metabolite, and DNA-processing

Diversity and evolution of chromatin proteins encoded by DNA viruses

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