Telomere functions: lessons from yeast

Telomeres are specialized DNA protein structures that form the ends of eukaryotic chromosomes. In yeast, loss of even a single telomere causes a prolonged, but transitory, cell-cycle arrest. During this arrest, many broken chromosomes acquire a new telomere by one of three pathways, although at the cost of a partial loss of heterozygosity. In addition, a substantial fraction of the chromosomes lacking a telomere is lost, which generates an aneuploid cell. In these cases, the broken chromosome is usually replicated and segregated for ten or more cell divisions in unstable form. Extrapolation from yeast suggests that the gradual loss of telomeric DNA that accompanies ageing in humans may initiate the kinds of chromosomal rearrangements and genetic changes that are associated with tumorigenesis.     

How centrioles work: lessons from green yeast

Centrioles are the organizing centers around which centrosomes assemble. Despite a century of study, the molecular details of centriole function and assembly remain largely unknown. Recent work has exploited the unique advantages of unicellular algae to reveal proteins that play central roles in centriole biology.     

Principles of bioactive lipid signalling: lessons from sphingolipids

It has become increasingly difficult to find an area of cell biology in which lipids do not have important, if not key, roles as signalling and regulatory molecules. The rapidly expanding field of bioactive lipids is exemplified by many sphingolipids, such as ceramide, sphingosine, sphingosine-1-phosphate (S1P), ceramide-1-phosphate and lyso-sphingomyelin, which have roles in the regulation of cell growth, death, senescence, adhesion, migration, inflammation, angiogenesis and intracellular trafficking. Deciphering the mechanisms of these varied cell functions necessitates an understanding of the complex pathways of sphingolipid metabolism and the mechanisms that regulate lipid generation and lipid action.     

Dissecting phosphorylation networks: lessons learned from yeast

Protein phosphorylation continues to be regarded as one of the most important post-translational modifications found in eukaryotes and has been implicated in key roles in the development of a number of human diseases. In order to elucidate roles for the 518 human kinases, phosphorylation has routinely been studied using the budding yeast Saccharomyces cerevisiae as a model system. In recent years, a number of technologies have emerged to globally map phosphorylation in yeast. In this article, we review these technologies and discuss how these phosphorylation mapping efforts have shed light on our understanding of kinase signaling pathways and eukaryotic proteomic networks in general.     

Principles of chromatin organization in yeast: relevance of polymer models to describe nuclear organization and dynamics

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Oxidative stress and aging: Learning from yeast lessons

The yeast Saccharomyces cerevisiae has played a vital role in the understanding of the molecular basis of aging and the relationship of aging process with oxidative stress (non-homeostatic accumulation of Reactive Oxygen Species, ROS). The mammalian and yeast antioxidant responses are similar and over 25 % of human-degenerative disease related genes have close homologues in yeast. The reduced genetic redundancy of yeast facilitates visualization of the effect of a deleted or mutated gene. By manipulating growth conditions, yeast cells can survive only fermenting (low ROS levels) or respiring (increased ROS levels), which facilitates the elucidation of the mechanisms involved with acquisition of tolerance to oxidative stress. Furthermore, the yeast databases are the most complete of all eukaryotic models. In this work, we highlight the value of S. cerevisiae as a model to investigate the oxidative stress response and its potential impact on aging and age-related diseases.     

Stress and prions: lessons from the yeast model

Yeast self-perpetuating amyloids (prions) provide a convenient model for studying the cellular control of highly ordered aggregates involved in mammalian protein assembly disorders. The very ability of an amyloid to propagate a prion state in yeast is determined by its interactions with the stress-inducible chaperone Hsp104. Prion formation and propagation are also influenced by other stress-related chaperones (Hsp70 and Hsp40), and by alterations of the protein trafficking and degradation networks. Some stress conditions induce prion formation or loss. It is proposed that prions arise as byproducts of the reversible assembly of highly ordered complexes, protecting certain proteins during unfavorable conditions.     

Activity-dependent organization of inhibitory circuits: lessons from the auditory system

In contrast to our detailed knowledge about the development and plasticity of excitatory neuronal circuits, little is known about the development of inhibitory circuits. Recent studies from the developing mammalian auditory system have revealed the presence of substantial activity-dependent synaptic reorganization in several inhibitory pathways. These studies importantly shed some new light on the general rules and cellular mechanisms that manage the organization of precise inhibitory circuits in the developing brain.     

Synthetic biology: lessons from engineering yeast MAPK signalling pathways

All living cells respond to external stimuli and execute specific physiological responses through signal transduction pathways. Understanding the mechanisms controlling signalling pathways is important for diagnosing and treating diseases and for reprogramming cells with desired functions. Although many of the signalling components in the budding yeast Saccharomyces cerevisiae have been identified by genetic studies, many features concerning the dynamic control of pathway activity, cross‐talk, cell‐to‐cell variability or robustness against perturbation are still incompletely understood. Comparing the behaviour of engineered and natural signalling pathways offers insight complementary to that achievable with standard genetic and molecular studies. Here, we review studies that aim at a deeper understanding of signalling design principles and generation of novel signalling properties by engineering the yeast mitogen‐activated protein kinase (MAPK) pathways. The underlying approaches can be applied to other organisms including mammalian cells and offer opportunities for building synthetic pathways and functionalities useful in medicine and biotechnology.     

Protein folding diseases and neurodegeneration: lessons learned from yeast

Budding yeast Saccharomyces cerevisiae has proven to be a valuable model organism for studying fundamental cellular processes across the eukaryotic kingdom including man. In this respect, complementation assays, in which the yeast protein is replaced by a homologous protein from another organism, have been very instructive. A newer trend is to use the yeast cell factory as a toolbox to understand cellular processes controlled by proteins for which the yeast lacks functional counterparts. An increasing number of studies have indicated that S. cerevisiae is a suitable model system to decipher molecular mechanisms involved in a variety of neurodegenerative disorders caused by aberrant protein folding. Here we review the current knowledge gained by the use of so-called humanized yeasts in the field of Huntington's, Parkinson's and Alzheimer's diseases.     

Ypt/Rab GTPases: Principles learned from yeast

Abstract

Ypt/Rab GTPases are key regulators of all membrane trafficking events in eukaryotic cells. They act as molecular switches that attach to membranes via lipid tails to recruit their multiple downstream effectors, which mediate vesicular transport. Originally discovered in yeast as Ypts, they were later shown to be conserved from yeast to humans, where Rabs are relevant to a wide array of diseases. Major principles learned from our past studies in yeast are currently accepted in the Ypt/Rab field including: (i) Ypt/Rabs are not transport-step specific, but are rather compartment specific, (ii) stimulation by nucleotide exchangers, GEFs, is critical to their function, whereas GTP hydrolysis plays a role in their cycling between membranes and the cytoplasm for multiple rounds of action, (iii) they mediate diverse functions ranging from vesicle formation to vesicle fusion and (iv) they act in GTPase cascades to regulate intracellular trafficking pathways. Our recent studies on Ypt1 and Ypt31/Ypt32 and their modular GEF complex TRAPP raise three exciting novel paradigms for Ypt/Rab function: (a) coordination of vesicular transport substeps, (b) integration of individual transport steps into pathways and (c) coordination of different transport pathways. In addition to its amenability to genetic analysis, yeast provides a superior model system for future studies on the role of Ypt/Rabs in traffic coordination due to the smaller proteome that results in a simpler traffic grid. We propose that different types of coordination are important also in human cells for fine-tuning of intracellular trafficking, and that coordination defects could result in disease.     

The molecular bases for copper uptake and distribution: lessons from yeast

Copper exists in two oxidation states, cuprous (Cu1+) and cupric (Cu2+), which, respectively, can donate or accept electrons. The fact that copper has two readily interconvertible redox states makes it a catalytic co-factor for many important enzymes. Over the past years, work in a number of laboratories has clearly demonstrated that studies in yeast have served as a springboard for identifying cellular components and processes involved in copper uptake and distribution. In several cases, it has been shown that mammalian proteins are capable of functionally replacing yeast proteins, thereby revealing their remarkable functional conservation. For high-affinity copper transport into cells, it has been shown that copper transporters of the Ctr family are required. Upon entering the cell, copper is partitioned to different proteins and into different compartments within the cell. Given the potential toxicity of copper, specialized proteins bind copper after it enters the cell and subsequently donate the bound copper to their corresponding recipient proteins. Three copper-binding proteins, Ccs1, Cox17, and Atx1, have been identified that serve as "copper chaperones" to deliver copper. double dagger.     

Autophagic recycling: lessons from yeast help define the process in plants

The autophagic engulfment of cytoplasm and organelles and their delivery to the vacuole have long been speculated to play an essential role in bulk protein turnover in plants. Until recently, however, the importance and the mechanism(s) of action of these processes have remained obscure. Aided by the discovery of numerous orthologs of the yeast AUTOPHAGY (ATG) protein system in Arabidopsis, significant advances have been now made in understanding these processes. Both reverse genetic analyses of the Arabidopsis ATG genes and the use of the encoded proteins as cytological markers have confirmed the presence of autophagy in plants and have demonstrated its importance in nutrient recycling, especially during senescence and growth under carbon- or nitrogen-limiting conditions.     

Defects in cytochrome oxidase assembly in humans: lessons from yeast.

The biogenesis of the inner mitochondrial membrane enzyme cytochrome c oxidase (COX) is a complex process that requires the actions of ancillary proteins, collectively called assembly factors. Studies with the yeast Saccharomyces cerevisiae have provided considerable insight into the COX assembly pathway and have proven to be a fruitful model for understanding the molecular bases for inherited COX deficiencies in humans. In this review, we focus on critical steps in the COX assembly pathway. These processes are conserved from yeast to humans and are known to be involved in the etiology of human COX deficiencies. The contributions from our studies in yeast suggest that this organism remains an excellent model system for delineating the molecular mechanisms underlying COX assembly defects in humans. Current progress suggests that a complete picture of COX assembly will be achieved in the near future.