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How the ER-associated degradation (ERAD) machinery accurately identifies terminally misfolded proteins is poorly understood. For luminal ERAD substrates, this recognition depends on their folding and glycosylation status as well as on the conserved ER lectin Yos9p. Here we show that Yos9p is part of a stable complex that organizes key components of ERAD machinery on both sides of the ER membrane,...
Development and homeostasis of the cardiovascular system require intimate interactions between endothelial and smooth muscle cells, which form a seamless circulatory network. We show that histone deacetylase 7 (HDAC7) is specifically expressed in the vascular endothelium during early embryogenesis, where it maintains vascular integrity by repressing the expression of matrix metalloproteinase (MMP)...
Small RNAs are essential for cell integrity, regulating gene expression at the levels of translation, RNA degradation, and chromatin. A series of recent reports show that the germlines of mammals and flies contain unique classes of small RNAs with potential functions in spermatogenesis and genome stability. Another study explores how tissue-specific expression of a small RNA is achieved. Together...
Crossovers produced by homologous recombination promote accurate chromosome segregation in meiosis and are controlled such that at least one forms per chromosome pair and multiple crossovers are widely spaced. Recombination initiates with an excess number of double-strand breaks made by Spo11 protein. Thus, crossover control involves a decision by which some breaks give crossovers while others follow...
Sirtuins have been the focus of intense scrutiny since the discovery of Sir2 as a yeast longevity factor. Functioning as either deacetylases or ADP ribosylases, Sirtuins are regulated by the cofactor NAD and thus may serve as sensors of the metabolic state of the cell and organism. Here we examine the roles of Sirtuins in diverse eukaryotic species, with special emphasis on their links to aging and...
A model of hematopoietic development wherein multipotentiality is conserved until segregation of myeloid and lymphoid potential has recently been challenged, proposing that megakaryocyte/erythrocyte (MegE) potential is lost in Flk2/Flt3-expressing early progenitors. Here, we used sensitive in vivo approaches to quantitatively and kinetically assess the MegE potential of hematopoietic stem cells and...
Many misfolded endoplasmic reticulum (ER) proteins are eliminated by ERAD, a process in which substrates are polyubiquitylated and moved into the cytosol for proteasomal degradation. We have identified in S. cerevisiae distinct ubiquitin-ligase complexes that define different ERAD pathways. Proteins with misfolded ER-luminal domains use the ERAD-L pathway, in which the Hrd1p/Hrd3p ligase forms a near...
Numerous factors are involved in the eradication of misfolded proteins, yet how these factors achieve substrate specificity remains unclear. In this issue of Cell, Denic et al. (2006) and Carvalho et al. (2006) report that two distinct protein complexes at the endoplasmic reticulum membrane are responsible for the recognition and degradation of specific subsets of protein substrates.
Cellular senescence is a stable state of proliferative arrest that provides a barrier to malignant transformation and contributes to the antitumor activity of certain chemotherapies. Senescent cells can accumulate senescence-associated heterochromatic foci (SAHFs), which may provide a chromatin buffer that prevents activation of proliferation-associated genes by mitogenic transcription factors. Surprisingly,...
Cystic fibrosis arises from the misfolding and premature degradation of CFTRΔF508, a Cl − ion channel with a single amino acid deletion. Yet, the quality-control machinery that selects CFTRΔF508 for degradation and the mechanism for its misfolding are not well defined. We identified an ER membrane-associated ubiquitin ligase complex containing the E3 RMA1, the E2 Ubc6e, and Derlin-1 that cooperates...
Epidermal lineage commitment occurs when multipotent stem cells are specified to three lineages: the epidermis, the hair follicle, and the sebaceous gland (SG). How and when a lineage becomes specified remains unknown. Here, we report the existence of a population of unipotent progenitor cells that reside in the SG and express the transcriptional repressor Blimp1. Using cell-culture studies and genetic...
Discovering target and off-target effects of specific compounds is critical to drug discovery and development. We generated a compendium of “chemical-genetic interaction” profiles by testing the collection of viable yeast haploid deletion mutants for hypersensitivity to 82 compounds and natural product extracts. To cluster compounds with a similar mode-of-action and to reveal insights into the cellular...
Small-molecule hormones govern every aspect of the biology of plants. Many processes, such as growth, are regulated in similar ways by multiple hormones, and recent studies have revealed extensive crosstalk among different hormonal signaling pathways. These results have led to the proposal that a common set of signaling components may integrate inputs from multiple hormones to regulate growth. In...
Symbiotic bacteria are important in animal hosts, but have been largely overlooked as they have proved difficult to culture in the laboratory. Approaches such as comparative genomics and real-time PCR have provided insights into the molecular mechanisms that underpin symbiont-host interactions. Studies on the heritable symbionts of insects have yielded valuable information about how bacteria infect...
In this issue of Cell, Murgia et al. (2006) confirm that the infectious agent of canine transmissible venereal tumor is the cancer cell itself and that the tumor is clonal in origin. Their findings have implications for understanding the relationship between genome instability and transmissible cancer and for conservation biology, canine genomics, and companion animal medicine.
Gap genes encode transcription factors involved in the patterning of the head-tail axis of insect embryos. In this issue of Cell, Savard et al. (2006) identify a beetle gap gene, mille-pattes, that encodes an unusual polycistronic transcript predicted to produce four conserved peptides. These results have interesting implications for the control of embryonic patterning in insects.
Caspase activation has been extensively studied in the context of apoptosis. However, caspases also control other cellular functions, although the mechanisms regulating caspases in nonapoptotic contexts remain obscure. Drosophila IAP1 (DIAP1) is an endogenous caspase inhibitor that is crucial for regulating cell death during development. Here we describe Drosophila IKK-related kinase (DmIKKɛ) as a...
Two new papers (Kuranaga et al., 2006; Oshima et al., 2006) describe a previously uncharacterized Drosophila kinase (DmIKKɛ) that regulates the abundance of DIAP1, a protein best known for its ability to inhibit apoptosis. However, DmIKKɛ-mediated degradation of DIAP1 does not regulate apoptosis as might be predicted but instead regulates actin dynamics, cell morphology, and the differentiation of...
The Chk2-p53-PUMA pathway is a major regulator of DNA-damage-induced apoptosis in response to double-strand breaks in vivo. Through analysis of 53BP1 complexes we have discovered a new ubiquitin protease, USP28, which regulates this pathway. Using a human cell line that faithfully recapitulated the Chk2-p53-PUMA pathway, we show that USP28 is required to stabilize Chk2 and 53BP1 in response to DNA...
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