Person: Budnik, Bogdan
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Budnik
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Bogdan
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Budnik, Bogdan
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Publication Quantifying Condition-Dependent Intracellular Protein Levels Enables High-Precision Fitness Estimates(Public Library of Science, 2013) Geiler-Samerotte, Kerry A.; Hashimoto, Tatsunori; Dion, Michael; Budnik, Bogdan; Airoldi, Edoardo; Drummond, D. AllanCountless studies monitor the growth rate of microbial populations as a measure of fitness. However, an enormous gap separates growth-rate differences measurable in the laboratory from those that natural selection can distinguish efficiently. Taking advantage of the recent discovery that transcript and protein levels in budding yeast closely track growth rate, we explore the possibility that growth rate can be more sensitively inferred by monitoring the proteomic response to growth, rather than growth itself. We find a set of proteins whose levels, in aggregate, enable prediction of growth rate to a higher precision than direct measurements. However, we find little overlap between these proteins and those that closely track growth rate in other studies. These results suggest that, in yeast, the pathways that set the pace of cell division can differ depending on the growth-altering stimulus. Still, with proper validation, protein measurements can provide high-precision growth estimates that allow extension of phenotypic growth-based assays closer to the limits of evolutionary selection.Publication Discovery of Human sORF-Encoded Polypeptides (SEPs) in Cell Lines and Tissue(American Chemical Society, 2014) Ma, Jiao; Ward, Carl; Jungreis, Irwin; Slavoff, Sarah A.; Schwaid, Adam G.; Neveu, John; Budnik, Bogdan; Kellis, Manolis; Saghatelian, AlanThe existence of nonannotated protein-coding human short open reading frames (sORFs) has been revealed through the direct detection of their sORF-encoded polypeptide (SEP) products. The discovery of novel SEPs increases the size of the genome and the proteome and provides insights into the molecular biology of mammalian cells, such as the prevalent usage of non-AUG start codons. Through modifications of the existing SEP-discovery workflow, we discover an additional 195 SEPs in K562 cells and extend this methodology to identify novel human SEPs in additional cell lines and human tissue for a final tally of 237 new SEPs. These results continue to expand the human genome and proteome and demonstrate that SEPs are a ubiquitous class of nonannotated polypeptides that require further investigation.Publication Constant Growth Rate Can Be Supported by Decreasing Energy Flux and Increasing Aerobic Glycolysis(Elsevier BV, 2014) Slavov, Nikolai; Budnik, Bogdan; Schwab, David; Airoldi, Edoardo; van Oudenaarden, AlexanderFermenting glucose in the presence of enough oxygen to support respiration, known as aerobic glycolysis, is believed to maximize growth rate. We observed increasing aerobic glycolysis during exponential growth, suggesting additional physiological roles for aerobic glycolysis. We investigated such roles in yeast batch cultures by quantifying \(O_2\) consumption, \(CO_2\) production, amino acids, mRNAs, proteins, posttranslational modifications, and stress sensitivity in the course of nine doublings at constant rate. During this course, the cells support a constant biomass-production rate with decreasing rates of respiration and ATP production but also decrease their stress resistance. As the respiration rate decreases, so do the levels of enzymes catalyzing rate-determining reactions of the tricarboxylic-acid cycle (providing NADH for respiration) and of mitochondrial folate-mediated NADPH production (required for oxidative defense). The findings demonstrate that exponential growth can represent not a single metabolic/physiological state but a continuum of changing states and that aerobic glycolysis can reduce the energy demands associated with respiratory metabolism and stress survival.Publication Reversible, Specific, Active Aggregates of Endogenous Proteins Assemble upon Heat Stress(Elsevier BV, 2015) Wallace, Edward W.J.; Kear-Scott, Jamie L.; Pilipenko, Evgeny V.; Schwartz, Michael H.; Laskowski, Pawel R.; Rojek, Alexandra E.; Katanski, Christopher D.; Riback, Joshua A.; Dion, Michael; Franks, Alexander M.; Airoldi, Edoardo; Pan, Tao; Budnik, Bogdan; Drummond, D. AllanHeat causes protein misfolding and aggregation, and in eukaryotic cells triggers aggregation of proteins and RNA into stress granules. We have carried out extensive proteomic studies to quantify heat-triggered aggregation and subsequent disaggregation in budding yeast, identifying more than 170 endogenous proteins aggregating within minutes of heat shock in multiple subcellular compartments. We demonstrate that these aggregated proteins are not misfolded and destined for degradation. Stable-isotope labeling reveals that even severely aggregated endogenous proteins are disaggregated without degradation during recovery from shock, contrasting with the rapid degradation observed for exogenous thermolabile proteins. Although aggregation likely inactivates many cellular proteins, in the case of a heterotrimeric aminoacyl-tRNA synthetase complex, the aggregated proteins remain active with unaltered fidelity. We propose that most heat-induced aggregation of mature proteins reflects the operation of an adaptive, autoregulatory process of functionally significant aggregate assembly and disassembly that aids cellular adaptation to thermal stress.Publication Systems-Level Response to Point Mutations in a Core Metabolic Enzyme Modulates Genotype-Phenotype Relationship(Elsevier BV, 2015) Bershtein, Shimon; Choi, Jeong-Mo; Bhattacharyya, Sanchari; Budnik, Bogdan; Shakhnovich, EugeneLinking the molecular effects of mutations to fitness is central to understanding evolutionary dynamics. Here we establish a quantitative relation between the global effect of mutations on the E. coli proteome and bacterial fitness. We created E. coli strains with specific destabilizing mutations in the chromosomal folA gene encoding dihydrofolate reductase (DHFR) and quantified the ensuing changes in the abundances of 2000+ E. coli proteins in mutant strains using tandem mass tags with subsequent LC-MS/MS. mRNA abundances in the same E. coli strains were also quantified. The proteomic effects of mutations in DHFR are quantitatively linked to phenotype: the standard deviations of the distributions of logarithms of relative (to wild-type) protein abundances anti-correlate with bacterial growth rates. Proteomes hierarchically cluster first by media conditions, and within each condition, by the severity of the perturbation to DHFR function. These results highlight the importance of a systems-level layer in the genotype-phenotype relationship.