Need-Based Up-Regulation of Protein Levels in Response to Deletion of Their Duplicate Genes

DeLuna, Alexander; Springer, Michael; Kirschner, Marc W.; Kishony, Roy

doi:10.1371/journal.pbio.1000347

Cited by 89 publications

(95 citation statements)

References 66 publications

(74 reference statements)

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“…Similarly, in agreement with DeLuna et al (27), the model predicts little dosage compensation if we delete a copy of a gene for a gratuitous protein (Fig. 2C).…”

Section: Applicationssupporting

confidence: 91%

“…We considered whether dosage compensation could arise from the global coupling of gene expression and the negative feedback generated by the trade-offs comprising the model. For example, DeLuna et al (27) examined dosage compensation in over 200 genes in budding yeast and found that increased expression of a paralog upon deletion of its duplicate occurs only for genes required for growth.…”

Section: Applicationsmentioning

confidence: 99%

“…For a system not constrained by cellular trade-offs and so with independent expression from each gene, levels of protein x in the deletion strain would be half the levels of protein x in the "wild-type" strain where w x is unchanged. Dosage compensation occurs if these two quantities are not equal and can be quantified using the "responsiveness" (27): the log 2 of the ratio of the levels of protein in the deletion strain to half the levels of protein in the wild-type strain. A system with independent gene expression would have a responsiveness of zero.…”

Section: Applicationsmentioning

confidence: 99%

“…Whether this global regulation is the mechanism behind the observations of DeLuna et al (27), however, requires further research: Specific regulation, such as end-product inhibition of enzymatic pathways, is a possible alternative. Exploiting the trade-offs for host-aware design of synthetic circuits.…”

Section: Applicationsmentioning

confidence: 99%

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Mechanistic links between cellular trade-offs, gene expression, and growth

Weiße

Oyarzún

Danos

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

376

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Intracellular processes rarely work in isolation but continually interact with the rest of the cell. In microbes, for example, we now know that gene expression across the whole genome typically changes with growth rate. The mechanisms driving such global regulation, however, are not well understood. Here we consider three trade-offs that, because of limitations in levels of cellular energy, free ribosomes, and proteins, are faced by all living cells and we construct a mechanistic model that comprises these trade-offs. Our model couples gene expression with growth rate and growth rate with a growing population of cells. We show that the model recovers Monod's law for the growth of microbes and two other empirical relationships connecting growth rate to the mass fraction of ribosomes. Further, we can explain growth-related effects in dosage compensation by paralogs and predict host-circuit interactions in synthetic biology. Simulating competitions between strains, we find that the regulation of metabolic pathways may have evolved not to match expression of enzymes to levels of extracellular substrates in changing environments but rather to balance a trade-off between exploiting one type of nutrient over another. Although coarse-grained, the trade-offs that the model embodies are fundamental, and, as such, our modeling framework has potentially wide application, including in both biotechnology and medicine.systems biology | synthetic biology | mathematical cell model | host-circuit interactions | evolutionarily stable strategy I ntracellular processes rarely work in isolation but continually interact with the rest of the cell. Yet often we study cellular processes with the implicit assumption that the remainder of the cell can either be ignored or provides a constant, background environment. Work in both systems and synthetic biology is, however, showing that this assumption is weak, at best. In microbes, growth rate can affect the expression both of single genes (1, 2) and across the entire genome (3-6). Specific control by transcription factors seems to be complemented by global, unspecific regulation that reflects the physiological state of the cell (5-7). Correspondingly, progress in synthetic biology is limited by two-way interactions between synthetic circuits and the host cell that cannot be designed away (8, 9).These phenomena are thought to arise from trade-offs where commitment of a finite intracellular resource to one response necessarily reduces the commitment of that resource to another response. A trade-off in the allocation of ribosomes has been suggested to underlie global gene regulation (2, 5). Similarly, depletion of finite resources and competition for cellular processes is thought to explain the failure of some synthetic circuits (8). Such circuits "load" the host cell, which can induce physiological responses that further degrade the function of the circuit (10). Our understanding of such trade-offs, however, is mostly phenomenological.Here we take an alternative approach and ask what new insi...

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“…Similarly, in agreement with DeLuna et al (27), the model predicts little dosage compensation if we delete a copy of a gene for a gratuitous protein (Fig. 2C).…”

Section: Applicationssupporting

confidence: 91%

Section: Applicationsmentioning

confidence: 99%

Section: Applicationsmentioning

confidence: 99%

Section: Applicationsmentioning

confidence: 99%

See 2 more Smart Citations

Mechanistic links between cellular trade-offs, gene expression, and growth

Weiße

Oyarzún

Danos

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

376

500

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“…4A) and flow cytometry analysis. LEU9 expression and ␣-IPMS activity were enhanced 3-to 5-fold in a leu4⌬ mutant background, indicating that, as has been previously observed for other paralogous pairs, deletion of one of the paralogs causes the upregulation of its counterpart (36).…”

Section: Leu4⌬ Mutants Accumulate Larger Leucine Pools Than the Wildtsupporting

confidence: 73%

Diversification of Paralogous α-Isopropylmalate Synthases by Modulation of Feedback Control and Hetero-Oligomerization in Saccharomyces cerevisiae

et al. 2015

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Production of ␣-isopropylmalate (␣-IPM) is critical for leucine biosynthesis and for the global control of metabolism. The budding yeast Saccharomyces cerevisiae has two paralogous genes, LEU4 and LEU9, that encode ␣-IPM synthase (␣-IPMS) isozymes.Little is known about the biochemical differences between these two ␣-IPMS isoenzymes. Here, we show that the Leu4 homodimer is a leucine-sensitive isoform, while the Leu9 homodimer is resistant to such feedback inhibition. The leu4⌬ mutant, which expresses only the feedback-resistant Leu9 homodimer, grows slowly with either glucose or ethanol and accumulates elevated pools of leucine; this phenotype is alleviated by the addition of leucine. Transformation of the leu4⌬ mutant with a centromeric plasmid carrying LEU4 restored the wild-type phenotype. Bimolecular fluorescent complementation analysis showed that Leu4-Leu9 heterodimeric isozymes are formed in vivo. Purification and kinetic analysis showed that the hetero-oligomeric isozyme has a distinct leucine sensitivity behavior. Determination of ␣-IPMS activity in ethanol-grown cultures showed that ␣-IPM biosynthesis and growth under these respiratory conditions depend on the feedback-sensitive Leu4 homodimer. We conclude that retention and further diversification of two yeast ␣-IPMSs have resulted in a specific regulatory system that controls the leucine-␣-IPM biosynthetic pathway by selective feedback sensitivity of homomeric and heterodimeric isoforms. The Leu4 and Leu9 ␣-isopropylmalate synthases (␣-IPMSs), paralogous isozymes from Saccharomyces cerevisiae, catalyze the first committed step of leucine biosynthesis: the synthesis of ␣-isopropylmalate (␣-IPM) from acetyl coenzyme A (acetylCoA) and ␣-ketoisovalerate (␣-KIV). This reaction is carried out in the mitochondria (1-8), and ␣-IPM is then transported from the mitochondria to the cytosol by the yeast oxaloacetate/sulfate carrier Oac1 (9). The concerted action of Leu1 and Leu2 converts ␣-IPM to ␣-ketoisocaproate, the immediate precursor of leucine; these reactions are performed in the cytoplasm (8). The last step in leucine biosynthesis is carried out on both the mitochondria and the cytoplasm through the action of the differentially localized Bat1 or Bat2 aminotransferase (10) (Fig. 1). Most of the ␣-IPMS activity in wild-type S. cerevisiae cells is provided by the mitochondrially localized LEU4-encoded isozyme and not by the Leu4 (Leu4 s) isoform, which naturally lacks the mitochondrial import sequence and is thus localized in the cytosol (1, 2).Leu4 enzymatic activity is inhibited by leucine and CoA, and the amino acid residues responsible for this property have been identified (7). Although no detailed biochemical characterization of the LEU9-encoded isozyme has been performed, it has been shown that it is less sensitive to leucine inhibition than Leu4 is (3).It is noteworthy that the leucine biosynthesis intermediate ␣-IPM plays a dual cellular role. On the one hand, it acts as an intermediate in leucine biosynthesis (5, 6), and on the other, it acts as t...

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Molecular mechanisms of paralogous compensation and the robustness of cellular networks

Diss¹,

et al. 2013

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Robustness is the ability of a system to maintain its function despite environmental or genetic perturbation. Genetic robustness is a key emerging property of living systems and is achieved notably by the presence of partially redundant parts that result from gene duplication. Functional overlap between paralogs allows them to compensate for each other's loss, as commonly revealed by aggravating genetic interactions. However, the molecular mechanisms linking the genotype (loss of function of a gene) to the phenotype (genetic buffering by a paralog) are still poorly understood and the molecular aspects of this compensation are rarely addressed in studies of gene duplicates. Here, we review molecular mechanisms of functional compensation between paralogous genes, many of which from studies that were not meant to study this phenomenon. We propose a standardized terminology and, depending on whether or not the molecular behavior of the intact gene is modified in response to the deletion of its paralog, we classify mechanisms of compensation into passive and active events. We further describe three non-exclusive mechanisms of active paralogous compensation for which there is evidence in the literature: changes in abundance, in localization, and in protein interactions. This review will serve as a framework for the genetic and molecular analysis of paralogous compensation, one of the universal features of genetic systems.

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Need-Based Up-Regulation of Protein Levels in Response to Deletion of Their Duplicate Genes

Abstract: Duplicated genes compensate for loss of one of the paralogs by up-regulating the remaining paralog only under growth conditions in which paralog activity is required for survival.

Cited by 89 publications

References 66 publications

Mechanistic links between cellular trade-offs, gene expression, and growth

Mechanistic links between cellular trade-offs, gene expression, and growth

Diversification of Paralogous α-Isopropylmalate Synthases by Modulation of Feedback Control and Hetero-Oligomerization in Saccharomyces cerevisiae

Molecular mechanisms of paralogous compensation and the robustness of cellular networks

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