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Comparison of phylogenetically diverse ribonucleoprotein (RNP) enzymes and information about their biochemistry have stimulated hypotheses about their evolution. Instead of the canonical view, in which catalysis proceeds from ribozyme to RNP enzyme to protein enzyme, RNP enzymes and proteins are seen to share contemporary catalysis. Furthermore, the RNA components of RNP enzymes show no evidence of...
RNAs are versatile molecules capable of an array of functions. In addition to their role as information-carrying intermediaries in gene expression, they act as key catalytic, structural, and regulatory elements in the cell. As highlighted in this issue's Select, recent studies on RNA show how these molecules collaborate with proteins in essential biological processes such as pre-mRNA splicing, mRNA...
Cellular functions depend on numerous protein-coding and noncoding RNAs and the RNA-binding proteins associated with them, which form ribonucleoprotein complexes (RNPs). Mutations that disrupt either the RNA or protein components of RNPs or the factors required for their assembly can be deleterious. Alternative splicing provides cells with an exquisite capacity to fine-tune their transcriptome and...
Translational control in eukaryotic cells is critical for gene regulation during nutrient deprivation and stress, development and differentiation, nervous system function, aging, and disease. We describe recent advances in our understanding of the molecular structures and biochemical functions of the translation initiation machinery and summarize key strategies that mediate general or gene-specific...
Viruses are adept at evolving or co-opting genomic elements that allow them to maximize their replication potential in the infected host. This evolutionary plasticity makes viruses an invaluable system to identify new mechanisms used not only by viruses but also by vertebrate cells to modulate gene expression. Here, I discuss the identification and characterization of viral mRNA structures and noncoding...
MicroRNAs (miRNAs) may be important regulators of gene expression. By modulating oncogenic and tumor suppressor pathways they could, in principle, contribute to tumorigenesis. Consistent with this hypothesis, recurrent genetic and epigenetic alterations of individual miRNAs are found in some tumors. Functional studies are now elucidating the mechanism of action of putative oncogenic and tumor suppressor...
Heterochromatin is dynamically regulated during the cell cycle and in response to developmental signals. Recent findings from diverse systems suggest an extensive role for transcription in the assembly of heterochromatin, highlighting the emerging theme that transcription and noncoding RNAs can provide the initial scaffold for the formation of heterochromatin, which serves as a versatile recruiting...
The localization of mRNAs to subcellular compartments provides a mechanism for regulating gene expression with exquisite temporal and spatial control. Recent studies suggest that a large fraction of mRNAs localize to distinct cytoplasmic domains. In this Review, we focus on cis-acting RNA localization elements, RNA-binding proteins, and the assembly of mRNAs into granules that are transported by molecular...
Two scientists walk into a bar. After a pint and an exchange of pleasantries, one says to the other, “Where do you come from? Scientifically, I mean.” The queried scientist responds, “Out of the RNA world.” “Don't we all,” the asker responds chuckling. Fifteen years ago, the joke would have been made with a nod to the notion that life arose from an RNA-based precursor, the so-called “RNA world.” Yet...
Kinetochores couple chromosomes to the assembling and disassembling tips of microtubules, a dynamic behavior that is fundamental to mitosis in all eukaryotes but poorly understood. Genetic, biochemical, and structural studies implicate the Ndc80 complex as a direct point of contact between kinetochores and microtubules, but these approaches provide only a static view. Here, using techniques for manipulating...
Store-operated Ca 2+ channels activated by the depletion of Ca 2+ from the endoplasmic reticulum (ER) are a major Ca 2+ entry pathway in nonexcitable cells and are essential for T cell activation and adaptive immunity. After store depletion, the ER Ca 2+ sensor STIM1 and the CRAC channel protein Orai1 redistribute to ER-plasma membrane (PM) junctions, but the fundamental...
This issue's Immunology Select highlights recent studies that provide insight into the timing and regulation of both innate and adaptive immune responses. Recent work in the fruit fly shows that enhanced stem cell proliferation in the intestine maintains tissue homeostasis in the face of bacterial infection. Other recent findings include a new factor involved in regulatory T cell function, a role...
In 2007, the European Research Council (ERC) was launched amid much fanfare with the goal of spearheading Europe's aspirations to become the most dynamic and competitive knowledge-based society in the world. Here, we examine the results of the first two ERC calls for research grants and discuss the latest developments and the challenges that face this unique research council.
The TRIM-NHL family of proteins is conserved among metazoans and has been shown to regulate cell proliferation and development. In this issue, Hammell et al. (2009) and Schwamborn et al. (2009) identify two members of this protein family, NHL-2 in worms and TRIM32 in mice, as positive regulators of microRNA function.
Reversible protein phosphorylation is a signaling mechanism involved in all cellular processes. To create a systems view of the signaling apparatus in budding yeast, we generated an epistatic miniarray profile (E-MAP) comprised of 100,000 pairwise, quantitative genetic interactions, including virtually all protein and small-molecule kinases and phosphatases as well as key cellular regulators. Quantitative...
Tumor blood vessels deliver oxygen poorly, thereby contributing to tumor hypoxia and upregulation of proangiogenic cytokines in an escalating feedback loop. Mazzone et al. (2009) now show that reducing the amount of a protein involved in endothelial oxygen sensing leads to changes in endothelial cell shape that interrupt this feedback loop and reduce tumor metastasis.
Activation of plasma membrane calcium channels by depletion of endoplasmic reticulum (ER) calcium stores is important for calcium entry in many cell types. Park et al. (2009) now show that direct binding of the ER protein STIM to tetramers of the Orai1 calcium channel in the plasma membrane triggers opening of this channel.
A key function of blood vessels, to supply oxygen, is impaired in tumors because of abnormalities in their endothelial lining. PHD proteins serve as oxygen sensors and may regulate oxygen delivery. We therefore studied the role of endothelial PHD2 in vessel shaping by implanting tumors in PHD2 +/− mice. Haplodeficiency of PHD2 did not affect tumor vessel density or lumen size, but normalized...
The small intestinal epithelium is the most rapidly self-renewing tissue of mammals. Proliferative cells are confined to crypts, while differentiated cell types predominantly occupy the villi. We recently demonstrated the existence of a long-lived pool of cycling stem cells defined by Lgr5 expression and intermingled with post-mitotic Paneth cells at crypt bottoms. We have now determined a gene signature...
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