Prp19/Pso4 Is an Autoinhibited Ubiquitin Ligase Activated by Stepwise Assembly of Three Splicing Factors

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Reactive oxygen species as mediators of cellular senescence

Aging has often been viewed as a random process arising from the accumulation of both genetic and epigenetic changes. Increasingly, the notion that aging is a stochastic process is being supplanted by the concept that maximum lifespan of an organism is tightly regulated. This knowledge has led to a growing overlap between classical signal transduction paradigms and the biology of aging. We review certain specific examples where these seemingly disparate disciplines intersect. In particular, we review the concept that intracellular reactive oxygen species function as signalling molecules and that oxidants play a central role as mediators of cellular senescence.     

Evolution of eukaryotic cell cycle regulation: stepwise addition of regulatory kinases and late advent of the CDKs

Protein kinases regulate a number of critical events in mitosis and meiosis. A study of the evolution of kinases involved in cell cycle control (CCC) might shed light on the evolution of the eukaryotic cell cycle. In particular, applying quantitative phylogenetic methods to key CCC kinases could provide information on the relative timing of gene duplication events. To investigate the evolution of CCC kinases, we constructed phylogenetic trees for the CDC28 family and performed statistical tests of the tree topology. This family includes the cyclin-dependent kinases (CDKs), which are key regulators of the eukaryotic cell cycle, as well as other CCC kinases. We found that CDKs and, in particular, the principal cell cycle regulator Cdc28p, branch off the phylogenetic tree at a late stage, after several other kinases involved in either mitosis or meiosis regulation. On the basis of this tree topology, it is proposed that, at early stages of evolution, the eukaryotic cell cycle was not controlled by CDKs and that only a subset of extant kinases, notably the DNA damage checkpoint kinase Chk1p, were in place. During subsequent evolution, a series of duplications of kinase genes occurred, gradually adding more kinases to the CCC system, the CDKs being among the last major additions.     

Aurora1 phosphorylation activity on histone H3 and its cross-talk with other post-translational histone modifications in Arabidopsis

The enzymological properties of AtAurora1, a kinase responsible for the cell cycle-dependent phosphorylation of histone H3 at S10, and its cross-talk with other post-translational histone modifications, were determined. In vitro phosphorylation of H3S10 by AtAurora1 is strongly increased by K9 acetylation, and decreased by K14 acetylation and T11 phosphorylation. However, S10 phosphorylation activity is unaltered by mono-, di- or trimethylation of K9. An interference of H3K9 dimethylation by SUVR4 occurs by a pre-existing phosphorylation at S10. Hence, cross-talk in plants exists between phosphorylation of H3S10 and methylation, acetylation or phosphorylation of neighbouring amino acid residues. AtAurora1 undergoes autophosphorylation in vivo regardless of the presence of substrate, and forms dimers in planta . Of the three ATP-competitive Aurora inhibitors tested, Hesperadin was most effective in reducing the in vivo kinase activity of AtAurora1. Hesperadin consistently inhibited histone H3S10 phosphorylation during mitosis in Arabidopsis cells, but did not affect other H3 post-translational modifications, suggesting a specific inhibition of AtAurora in vivo . Inactivation of AtAurora also caused lagging chromosomes in a number of anaphase cells, but, unlike the situation in mammalian cells, Hesperadin did not influence the microtubule dynamics in dividing cells.     

Moderate AMPA receptor clustering on the nanoscale can efficiently potentiate synaptic current

The prevailing view at present is that postsynaptic expression of the classical NMDA receptor-dependent long-term potentiation relies on an increase in the numbers of local AMPA receptors (AMPARs). This is thought to parallel an expansion of postsynaptic cell specializations, for instance dendritic spine heads, which accommodate synaptic receptor proteins. However, glutamate released into the synaptic cleft can normally activate only a hotspot of low-affinity AMPARs that occur in the vicinity of the release site. How the enlargement of the AMPAR pool is causally related to the potentiated AMPAR current remains therefore poorly understood. To understand possible scenarios of postsynaptic potentiation, here we explore a detailed Monte Carlo model of the typical small excitatory synapse. Simulations suggest that approximately 50% increase in the synaptic AMPAR current could be provided by expanding the existing AMPAR pool at the expense of 100–200% new AMPARs added at the same packing density. Alternatively, reducing the inter-receptor distances by only 30–35% could achieve a similar level of current potentiation without any changes in the receptor numbers. The NMDA receptor current also appears sensitive to the NMDA receptor crowding. Our observations provide a quantitative framework for understanding the ‘resource-efficient’ ways to enact use-dependent changes in the architecture of central synapses.     

Impairment of phagocytosis of apoptotic cells and its role in chronic airway diseases

Phagocytosis of dying cells is a complex and dynamic process coordinated by the interaction of many surface molecules, adaptors, and chemotactic molecules, and it is controlled at multiple levels. This well regulated clearance process is of utmost importance for the development and homeostasis of organisms because defective or inefficient phagocytosis may contribute to human pathologies. In this review we discuss recent advances in the knowledge of the molecular interactions involved in recognition and clearance of apoptotic cells and how derangement of these processes can contribute to the pathogenesis of chronic airway diseases such as chronic obstructive pulmonary disease, cystic fibrosis and asthma. We will briefly consider how different types of macrophages are implicated in chronic airway diseases. Finally, we will address possible therapeutic strategies, such as the use of macrolide antibiotics and statins, for modulating apoptotic cell clearance.