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The primary cilium is required for Sonic hedgehog (Shh) signaling in vertebrates. In contrast to mutants affecting ciliary assembly, mutations in the intraflagellar transport complex A (IFT-A) paradoxically cause increased Shh signaling. We previously showed that the IFT-A complex, in addition to its canonical role in retrograde IFT, binds to the tubby-like protein, Tulp3, and recruits it to cilia...
22q11.2 microdeletions result in specific cognitive deficits and schizophrenia. Analysis of Df(16)A +/− mice, which model this microdeletion, revealed abnormalities in the formation of neuronal dendrites and spines, as well as altered brain microRNAs. Here, we show a drastic reduction of miR-185, which resides within the 22q11.2 locus, to levels more than expected by a hemizygous deletion,...
The IκB kinase complex (IKK) is a key regulator of immune responses, inflammation, cell survival, and tumorigenesis. The prosurvival function of IKK centers on activation of the transcription factor NF-κB, whose target gene products inhibit caspases and prevent prolonged JNK activation. Here, we report that inactivation of the BH3-only protein BAD by IKK independently of NF-κB activation suppresses...
Establishment of oligodendrocyte identity is crucial for subsequent events of myelination in the CNS. Here, we demonstrate that activation of ATP-dependent SWI/SNF chromatin-remodeling enzyme Smarca4/Brg1 at the differentiation onset is necessary and sufficient to initiate and promote oligodendrocyte lineage progression and maturation. Genome-wide multistage studies by ChIP-seq reveal that oligodendrocyte-lineage...
Cu/Zn superoxide dismutase (SOD1) is an abundant enzyme that has been best studied as a regulator of antioxidant defense. Using the yeast Saccharomyces cerevisiae, we report that SOD1 transmits signals from oxygen and glucose to repress respiration. The mechanism involves SOD1-mediated stabilization of two casein kinase 1-gamma (CK1γ) homologs, Yck1p and Yck2p, required for respiratory repression...
Cell-type plasticity within a tumor has recently been suggested to cause a bidirectional conversion between tumor-initiating stem cells and nonstem cells triggered by an inflammatory stroma. NF-κB represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-κB’s function in tumor-initiating cells has not been examined yet. Using a genetic model of intestinal epithelial...
The sequence-specific transcription factor NF-Y binds the CCAAT box, one of the sequence elements most frequently found in eukaryotic promoters. NF-Y is composed of the NF-YA and NF-YB/NF-YC subunits, the latter two hosting histone-fold domains (HFDs). The crystal structure of NF-Y bound to a 25 bp CCAAT oligonucleotide shows that the HFD dimer binds to the DNA sugar-phosphate backbone, mimicking...
Stem and/or progenitor cells often generate distinct cell types in a stereotyped birth order and over time lose competence to specify earlier-born fates by unknown mechanisms. In Drosophila, the Hunchback transcription factor acts in neural progenitors (neuroblasts) to specify early-born neurons, in part by indirectly inducing the neuronal transcription of its target genes, including the hunchback...
Enhancers play a central role in precisely regulating the expression of developmentally regulated genes. However, the machineries required for enhancer-promoter communication have remained largely unknown. We have found that Ell3, a member of the Ell (eleven-nineteen lysine-rich leukemia gene) family of RNA Pol II elongation factors, occupies enhancers in embryonic stem cells. Ell3’s association with...
MDA5, a viral double-stranded RNA (dsRNA) receptor, shares sequence similarity and signaling pathways with RIG-I yet plays essential functions in antiviral immunity through distinct specificity for viral RNA. Revealing the molecular basis for the functional divergence, we report here the crystal structure of MDA5 bound to dsRNA, which shows how, using the same domain architecture, MDA5 recognizes...
Drosophila neural progenitor cells are competent to give rise to certain neuronal cell types only during a limited period of time. Kohwi et al. link the termination of early competence to changes in subnuclear organization of chromatin.
According to current models, once the cell has reached terminal differentiation, the enhancer repertoire is completely established and maintained by cooperatively acting lineage-specific transcription factors (TFs). TFs activated by extracellular stimuli operate within this predetermined repertoire, landing close to where master regulators are constitutively bound. Here, we describe latent enhancers,...
Cytosine methylation is involved in various biological processes such as silencing of transposable elements (TEs) and imprinting. Multiple pathways regulate DNA methylation in different sequence contexts, but the factors that regulate DNA methylation at a given site in the genome largely remain unknown. Here we have surveyed the methylomes of a comprehensive list of 86 Arabidopsis gene silencing mutants...
Telomere shortening impairs proliferation of transformed cells but also leads to cancer initiation by inducing chromosomal instability. Here, we discuss recent developments in our understanding of the role of telomeres in replication stress and how telomerase expression in somatic stem cells may affect genome integrity control and carcinogenesis.
Recent advances in G-protein-coupled receptor structural biology have provided only limited insight into the active conformations of these key signaling molecules. A paper from Nygaard et al. reveals the dynamic nature of GPCRs along the activation pathway by complementing NMR experiments with ultralong-timescale molecular dynamics simulations.
There are ∼650,000 Alu elements in transcribed regions of the human genome. These elements contain cryptic splice sites, so they are in constant danger of aberrant incorporation into mature transcripts. Despite posing a major threat to transcriptome integrity, little is known about the molecular mechanisms preventing their inclusion. Here, we present a mechanism for protecting the human transcriptome...
Self-interacting BAX proteins permeabilize outer mitochondrial membranes to trigger apoptotic cell death. Czabotar et al. present two revealing structures of BAX dimers: one dimer has an activator BH3 helix bound into its canonical cleft, and the other dimer exposes a planar hydrophobic face potentially critical for membrane interactions.
Changes in DNA copy number, whether confined to specific genes or affecting whole chromosomes, have been identified as causes of diseases and developmental abnormalities and as sources of adaptive potential. Here, we discuss the costs and benefits of DNA copy-number alterations. Changes in DNA copy number are largely detrimental. Amplifications or deletions of specific genes can elicit discrete defects...
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