Integrative studies put cell wall synthesis on the yeast functional map

The fungal cell wall field, traditionally focused on polysaccharide composition and synthesis, retains a certain static architectural imagery of structural rigidity and integrity, with the wall offering protection from a harsh environment. This picture of the wall is increasingly changing to that of a bustling construction site, as research uncovers the organizational complexity of its assembly. With recent molecular and genomic studies on Saccharomyces cerevisiae, cell wall synthesis and biology appear increasingly to be dynamic and adaptable processes that are fully integrated with the underlying cytoskeletal and polarity machinery that drive cell cycle progression.     

Cell cycle and differentiation

The development of multicellular organisms relies on the temporal and spatial control of cell proliferation and cell growth. The relationship between cell-cycle progression and development is complex and characterized by mutual dependencies. On the level of the individual cell, this interrelationship has implications for pattern formation and cell morphogenesis. On a supercellular level, this interrelationship affects meristem function and organ growth. Often, developmental signals not only direct cell-cycle progression but also set the frame for cell-cycle regulation by determining cell-type-specific cell-cycle modes. In other cases, however, cell-cycle progression appears to be required for the further differentiation of some cell types. There are also examples in which cell cycle and differentiation seem to be controlled at the same level and progress rather independently from each other or are linked by the same regulator or pathway. Furthermore, different relationships between cell cycle and differentiation can be combined in a succession of events during development, leading to complex developmental programs.     

Aging and genetic instability in yeast

There is a striking link between increasing age and the incidence of cancer in humans. One of the hallmarks of cancer, genomic instability, has been observed in all types of organisms. In the yeast Saccharomyces cerevisiae, it was recently discovered that during the replicative lifespan, aging cells switch to a state of high genomic instability that persists until they die. In considering these and other recent results, we suggest that accumulation of oxidatively damaged protein in aging cells results in the loss of function of gene products critical for maintaining genome integrity. Determining the identity of these proteins and how they become damaged represents a new challenge for understanding the relationship between age and genetic instability.     

Evolutionary impact of human Alu repetitive elements

Early studies of human Alu retrotransposons focused on their origin, evolution and biological properties, but current focus is shifting toward the effect of Alu elements on evolution of the human genome. Recent analyses indicate that numerous factors have affected the chromosomal distribution of Alu elements over time, including male-driven insertions, deletions and rapid CpG mutations after their retrotransposition. Unequal crossing over between Alu elements can lead to local mutations or to large segmental duplications responsible for genetic diseases and long-term evolutionary changes. Alu elements can also affect human (primate) evolution by introducing alternative splice sites in existing genes. Studying the Alu family in a human genomic context is likely to have general significance for our understanding of the evolutionary impact of other repetitive elements in diverse eukaryotic genomes.     

Functional microcircuitry in the accumbens underlying drug addiction: insights from real-time signaling during behavior

An understanding of the neurobiological basis of drug addiction requires examination of real-time (subsecond) cellular and chemical responses in the brain reward system during drug-seeking and drug-taking behavior. Electrophysiological and electrochemical studies in the rodent nucleus accumbens have examined changes in cell firing and rapid dopamine signaling during crucial periods of behavioral responding for drugs, and show the associative nature of those signals. These findings are considered with respect to the functional microcircuitry in the nucleus accumbens that underlies goal-directed behavior and the role of this circuit in drug addiction.     

Small GTPases in vesicle trafficking

Plant small GTPases belonging to the Rop, Arf, and Rab families are regulators of vesicle trafficking. Rop GTPases regulate actin dynamics and modulate H(2)O(2) production in polar cell growth and pathogen defence. A candidate Rop GDP to Rop GTP exchange factor (RopGEF) SPIKE1 is involved in the morphogenesis of leaf epidermal cells. The ArfGEF GNOM regulates the endosomal recycling of the PIN proteins, which are involved in polar auxin transport. Intracellular localisation of small GTPases and functional studies using dominant mutant versions of Arf and Rab GTPases are defining novel plant-specific membrane compartments, especially those that participate in endosomal vesicle trafficking.     

The value-added genome: building and maintaining genomic cytosine methylation landscapes

Epigenetic marks, such as cytosine methylation and post-translational histone modifications, are important for interpreting and managing eukaryotic genomes. Recent genetic studies in plants have uncovered details on the different interwoven mechanisms that are responsible for specification of genomic cytosine methylation patterns. These mechanisms include targeting cytosine methylation using heterochromatic histone modifications and RNA guides. Genomic cytosine methylation patterns also reflect locus-specific demethylation initiated by specialized DNA glycosylases. While genetics continues to more fully define these mechanisms, genomic studies in Arabidopsis have yielded an unprecedented high-resolution view of how epigenetic marks are layered over a genome.     

Regulation of the meiotic cell cycle in oocytes

The mitotic and meiotic cell cycle share many regulators, but there are also important differences between the two processes. The meiotic maturation of Xenopus oocytes has proved useful for understanding the regulation of Cdc2-cyclin-B, a key activator of G2/M progression. New insights have been made recently into the signalling mechanisms that induce G2-arrested oocytes to resume and complete the meiotic cell cycle.     

A loss of function screen identifies nine new radiation susceptibility genes

Genomic instability is considered a hallmark of carcinogenesis, and dysfunction of DNA repair and cell cycle regulation in response to DNA damage caused by ionizing radiation are thought to be important factors in the early stages of genomic instability. We performed cell-based functional screening using an RNA interference library targeting 200 genes in human cells. We identified three known and nine new radiation susceptibility genes, eight of which are linked directly or potentially with cell cycle progression. Cell cycle analysis on four of the genes not previously linked to cell cycle progression demonstrated that one, ZDHHC8, was associated with the G₂/M checkpoint in response to DNA damage. Further study of the 12 radiation susceptibility genes identified in this screen may help to elucidate the molecular mechanisms of cell cycle progression, DNA repair, cell death, cell growth and genomic instability, and to develop new radiation sensitizing agents for radiotherapy.     

Cell polarity, intercellular signalling and morphogenetic cell movements in Myxococcus xanthus

In Myxococcus xanthus morphogenetic cell movements constitute the basis for the formation of spreading vegetative colonies and fruiting bodies in starving cells. M. xanthus cells move by gliding and gliding motility depends on two polarly localized engines, type IV pili pull cells forward, and slime extruding nozzle-like structures appear to push cells forward. The motility behaviour of cells provides evidence that the two engines are localized to opposite poles and that they undergo polarity switching. Several proteins involved in regulating polarity switching have been identified. The cell surface-associated C-signal induces the directed movement of cells into nascent fruiting bodies. Recently, the molecular nature of the C-signal molecule was elucidated and the motility parameters regulated by the C-signal were identified. From the effect of the C-signal on cell behaviour it appears that the C-signal inhibits polarity switching of the two motility engines. This establishes a connection between cell polarity, signalling by an intercellular signal and morphogenetic cell movements during fruiting body formation.     

A platypus' eye view of the mammalian genome

The genome of monotremes, like the animals themselves, is unique and strange. The importance of monotremes to genomics depends on their position as the earliest offshoot of the mammalian lineage. Although there has been controversy in the literature over the phylogenetic position of monotremes, this traditional interpretation is now confirmed by recent sequence comparisons. Characterizing the monotreme genome will therefore be important for studying the evolution and organization of the mammalian genome, and the proposal to sequence the platypus genome has been received enthusiastically by the genomics community. Recent investigations of X-chromosome inactivation, genomic imprinting and sex chromosome evolution provide good examples of the power of the monotreme genome to inform us about mammalian genome organization and evolution.     

The sema domain

The sema domain was first defined from sequence by Kolodkin and colleagues in the early 1990s, and constitutes the distinctive structural and functional element of semaphorins, their plexin receptors and the receptor tyrosine kinases MET and RON, three protein families with major roles in development, tissue regeneration and cancer. Recently determined crystal structures of two semaphorins (SEMA3A and SEMA4D) and the MET receptor have shown that the sema domain consists of a highly conserved variant form of the seven-blade beta-propeller fold. The structures, however, also suggest differences between these families with respect to the mode of dimerisation and the regions of the domain involved in ligand-receptor interactions. This reflects the considerable plasticity and adaptation of the sema domain in order to meet different binding requirements, properties that may underlie the vast array of ligand-receptor specificities and functions of the semaphorin superfamily.     

Spatial complexity of mechanisms controlling a bacterial cell cycle

Cell cycle progression in Caulobacter is governed by a multilayered regulatory network linking chromosome replication with polar morphogenesis and cell division. Temporal and spatial regulation have emerged as the central themes, with the abundance, activity and subcellular location of key structural and regulatory proteins changing over the course of the cell cycle. An additional layer of complexity was recently uncovered, showing that each segment of the chromosome is located at a specific cellular position both during and after the completion of DNA replication, raising the possibility that this positioning contributes to temporal and spatial control of gene expression.     

Innovative approaches to novel antibacterial drug discovery

Increasing antibiotic resistance in microorganisms and new emerging pathogens have become a major problem in our society. Rising to satisfy this urgent medical need is a recent confluence of powerful new drug discovery technologies: combinatorial chemistry; sequence and functional genomic analysis; and novel methods of high-throughput screening. The combination of these technologies will bring to bear untapped power in the search for new antimicrobials.     

Regulation of mitochondrial membrane permeabilization by BCL-2 family proteins and caspases

Mitochondria play an important role in the integration and transmission of cell death signals, activating caspases and other cell death execution events by releasing apoptogenic proteins from the intermembrane space. The BCL-2 family of proteins localize (or can be targeted) to mitochondria and regulate the permeability of the mitochondrial outer membrane to these apoptotic factors. Recent evidence suggests that multiple mechanisms may regulate the release of mitochondrial factors, some of which depend on the action of caspases.     

Three's company: component structures bring a closer view of tripartite drug efflux pumps

Bacterial multidrug resistance is a serious clinical problem and is commonly conferred by tripartite efflux 'pumps' in the prokaryotic cell envelope. Crystal structures of the three components of a drug efflux pump have now been solved: the outer membrane TolC exit duct in the year 2000, the inner membrane AcrB antiporter in 2002 and the periplasmic adaptor MexA in 2004. These structures have enhanced our understanding of the principles underlying pump assembly and operation, and present pumps as new drug targets.