NBS1 promotes the endonuclease activity of the MRE11-RAD50 complex by sensing CtIP phosphorylation
DNA end resection initiates DNA double-strand break repair by homologous recombination. MRE11-RAD50-NBS1 and phosphorylated CtIP perform the first resection step via MRE11-catalyzed endonucleolytic DNA cleavage. Human NBS1, more than its homologue Xrs2 in Saccharomyces cerevisiae, is crucial for this process, highlighting complex mechanisms that regulate the MRE11 nuclease in higher eukaryotes. Using a reconstituted system, we show here that NBS1, through its FHA and BRCT domains, functions as a sensor of CtIP phosphorylation. NBS1 then activates the MRE11-RAD50 nuclease through direct physical interactions with MRE11. In ...
Source: EMBO Journal - March 31, 2019 Category: Molecular Biology Authors: Anand, R., Jasrotia, A., Bundschuh, D., Howard, S. M., Ranjha, L., Stucki, M., Cejka, P. Tags: DNA Replication, Repair & Recombination Articles Source Type: research
Efficient mitotic checkpoint signaling depends on integrated activities of Bub1 and the RZZ complex
In conclusion, our results support an integrated model for the Mad1 receptors in which the primary role of RZZ is to localize Mad1 at kinetochores to generate the Mad1-Bub1 complex. (Source: EMBO Journal)
Source: EMBO Journal - March 31, 2019 Category: Molecular Biology Authors: Zhang, G., Kruse, T., Guasch Boldu, C., Garvanska, D. H., Coscia, F., Mann, M., Barisic, M., Nilsson, J. Tags: Cell Cycle Articles Source Type: research
Ssu72 phosphatase is a conserved telomere replication terminator
Telomeres, the protective ends of eukaryotic chromosomes, are replicated through concerted actions of conventional DNA polymerases and elongated by telomerase, but the regulation of this process is not fully understood. Telomere replication requires (Ctc1/Cdc13)-Stn1-Ten1, a telomeric ssDNA-binding complex homologous to RPA. Here, we show that the evolutionarily conserved phosphatase Ssu72 is responsible for terminating the cycle of telomere replication in fission yeast. Ssu72 controls the recruitment of Stn1 to telomeres by regulating Stn1 phosphorylation at Ser74, a residue located within its conserved OB-fold domain. Co...
Source: EMBO Journal - March 31, 2019 Category: Molecular Biology Authors: Escandell, J. M., Carvalho, E. S., Gallo-Fernandez, M., Reis, C. C., Matmati, S., Luis, I. M., Abreu, I. A., Coulon, S., Ferreira, M. G. Tags: DNA Replication, Repair & Recombination, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Extracellular matrix sensing by FERONIA and Leucine-Rich Repeat Extensins controls vacuolar expansion during cellular elongation in Arabidopsis thaliana
Cellular elongation requires the defined coordination of intra- and extracellular processes, but the underlying mechanisms are largely unknown. The vacuole is the biggest plant organelle, and its dimensions play a role in defining plant cell expansion rates. Here, we show that the increase in vacuolar occupancy enables cellular elongation with relatively little enlargement of the cytosol in Arabidopsis thaliana. We demonstrate that cell wall properties are sensed and impact on the intracellular expansion of the vacuole. Using vacuolar morphology as a quantitative read-out for intracellular growth processes, we reveal that ...
Source: EMBO Journal - March 31, 2019 Category: Molecular Biology Authors: Dünser, K., Gupta, S., Herger, A., Feraru, M. I., Ringli, C., Kleine-Vehn, J. Tags: Membrane & Intracellular Transport, Plant Biology Articles Source Type: research
BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses
BRD4 is a BET family protein that binds acetylated histones and regulates transcription. BET/BRD4 inhibitors block blood cancer growth and inflammation and serve as a new therapeutic strategy. However, the biological role of BRD4 in normal hematopoiesis and inflammation is not fully understood. Analysis of Brd4 conditional knockout (KO) mice showed that BRD4 is required for hematopoietic stem cell expansion and progenitor development. Nevertheless, BRD4 played limited roles in macrophage development and inflammatory response to LPS. ChIP-seq analysis showed that despite its limited importance, BRD4 broadly occupied the mac...
Source: EMBO Journal - March 31, 2019 Category: Molecular Biology Authors: Dey, A., Yang, W., Gegonne, A., Nishiyama, A., Pan, R., Yagi, R., Grinberg, A., Finkelman, F. D., Pfeifer, K., Zhu, J., Singer, D., Zhu, J., Ozato, K. Tags: Immunology, Stem Cells, Transcription Articles Source Type: research
Histidine is selectively required for the growth of Myc-dependent dedifferentiation tumours in the Drosophila CNS
This study suggests that perturbations in histidine metabolism selectively target neural tumours that grow via a dedifferentiation process involving large cell size increases driven by Myc. (Source: EMBO Journal)
Source: EMBO Journal - March 31, 2019 Category: Molecular Biology Authors: Froldi, F., Pachnis, P., Szuperak, M., Costas, O., Fernando, T., Gould, A. P., Cheng, L. Y. Tags: Cancer, Neuroscience Articles Source Type: research
Frozen-hydrated chromatin from metaphase chromosomes has an interdigitated multilayer structure
Cryo-electron tomography and small-angle X-ray scattering were used to investigate the chromatin folding in metaphase chromosomes. The tomographic 3D reconstructions show that frozen-hydrated chromatin emanated from chromosomes is planar and forms multilayered plates. The layer thickness was measured accounting for the contrast transfer function fringes at the plate edges, yielding a width of ~ 7.5 nm, which is compatible with the dimensions of a monolayer of nucleosomes slightly tilted with respect to the layer surface. Individual nucleosomes are visible decorating distorted plates, but typical plates are very d...
Source: EMBO Journal - March 31, 2019 Category: Molecular Biology Authors: Chicano, A., Crosas, E., Oton, J., Melero, R., Engel, B. D., Daban, J.-R. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Structural Biology Articles Source Type: research
The pluripotency factor NANOG controls primitive hematopoiesis and directly regulates Tal1
Progenitors of the first hematopoietic cells in the mouse arise in the early embryo from Brachyury-positive multipotent cells in the posterior-proximal region of the epiblast, but the mechanisms that specify primitive blood cells are still largely unknown. Pluripotency factors maintain uncommitted cells of the blastocyst and embryonic stem cells in the pluripotent state. However, little is known about the role played by these factors during later development, despite being expressed in the postimplantation epiblast. Using a dual transgene system for controlled expression at postimplantation stages, we found that Nanog bloc...
Source: EMBO Journal - March 31, 2019 Category: Molecular Biology Authors: Sainz de Aja, J., Menchero, S., Rollan, I., Barral, A., Tiana, M., Jawaid, W., Cossio, I., Alvarez, A., Carreno-Tarragona, G., Badia-Careaga, C., Nichols, J., Göttgens, B., Isern, J., Manzanares, M. Tags: Development & Differentiation, Transcription Articles Source Type: research
An ancient antisense-driven RNA switch drives plant sex determination
New work by Hisanaga et al (2019) uncovers the central module that regulates sexual dimorphism in haploid early land plants, opening doors toward understanding evolution of sex chromosomes in ancestors of diploid plants. (Source: EMBO Journal)
Source: EMBO Journal - March 14, 2019 Category: Molecular Biology Authors: Berger, F. Tags: Plant Biology, RNA Biology, Transcription News [amp ] Views Source Type: research
Boosting adult neurogenesis to enhance sensory performance
Although most mammalian neurons are born prenatally, there are at least a couple of specialised niches in the adult rodent brain that continually generate new neurons throughout life. The potential functions conferred by this process of adult neurogenesis, however, remain obscure, despite a sizeable literature exploring the links between alterations in neurogenic capacity and changes in behavioural ability. A new study by Bragado Alonso et al (2019) offers a novel viewpoint on this question by describing a particularly clean way to manipulate adult neurogenesis. Specifically altering cell cycle dynamics in adult neura...
Source: EMBO Journal - March 14, 2019 Category: Molecular Biology Authors: Lipovsek, M., Grubb, M. S. Tags: Neuroscience News [amp ] Views Source Type: research
ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination
Deubiquitination of NLRP3 has been suggested to contribute to inflammasome activation, but the roles and molecular mechanisms are still unclear. We here demonstrate that ABRO1, a subunit of the BRISC deubiquitinase complex, is necessary for optimal NLRP3-ASC complex formation, ASC oligomerization, caspase-1 activation, and IL-1β and IL-18 production upon treatment with NLRP3 ligands after the priming step, indicating that efficient NLRP3 activation requires ABRO1. Moreover, we report that ABRO1 deficiency results in a remarkable attenuation in the syndrome severity of NLRP3-associated inflammatory diseases, including ...
Source: EMBO Journal - March 14, 2019 Category: Molecular Biology Authors: Ren, G., Zhang, X., Xiao, Y., Zhang, W., Wang, Y., Ma, W., Wang, X., Song, P., Lai, L., Chen, H., Zhan, Y., Zhang, J., Yu, M., Ge, C., Li, C., Yin, R., Yang, X. Tags: Immunology, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
A cis-acting bidirectional transcription switch controls sexual dimorphism in the liverwort
Plant life cycles alternate between haploid gametophytes and diploid sporophytes. While regulatory factors determining male and female sexual morphologies have been identified for sporophytic reproductive organs, such as stamens and pistils of angiosperms, those regulating sex-specific traits in the haploid gametophytes that produce male and female gametes and hence are central to plant sexual reproduction are poorly understood. Here, we identified a MYB-type transcription factor, MpFGMYB, as a key regulator of female sexual differentiation in the haploid-dominant dioicous liverwort, Marchantia polymorpha. MpFGMYB is speci...
Source: EMBO Journal - March 14, 2019 Category: Molecular Biology Authors: Hisanaga, T., Okahashi, K., Yamaoka, S., Kajiwara, T., Nishihama, R., Shimamura, M., Yamato, K. T., Bowman, J. L., Kohchi, T., Nakajima, K. Tags: Plant Biology, RNA Biology, Transcription Articles Source Type: research
Unanchored tri-NEDD8 inhibits PARP-1 to protect from oxidative stress-induced cell death
NEDD8 is a ubiquitin-like protein that activates cullin-RING E3 ubiquitin ligases (CRLs). Here, we identify a novel role for NEDD8 in regulating the activity of poly(ADP-ribose) polymerase 1 (PARP-1) in response to oxidative stress. We show that treatment of cells with H2O2 results in the accumulation of NEDD8 chains, likely by directly inhibiting the deneddylase NEDP1. One chain type, an unanchored NEDD8 trimer, specifically bound to the second zinc finger domain of PARP-1 and attenuated its activation. In cells in which Nedp1 is deleted, large amounts of tri-NEDD8 constitutively form, resulting in inhibition of PARP-1 an...
Source: EMBO Journal - March 14, 2019 Category: Molecular Biology Authors: Keuss, M. J., Hjerpe, R., Hsia, O., Gourlay, R., Burchmore, R., Trost, M., Kurz, T. Tags: Autophagy & Cell Death, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Nuclear import of the DSCAM-cytoplasmic domain drives signaling capable of inhibiting synapse formation
DSCAM and DSCAML1 are immunoglobulin and cell adhesion-type receptors serving important neurodevelopmental functions including control of axon growth, branching, neurite self-avoidance, and neuronal cell death. The signal transduction mechanisms or effectors of DSCAM receptors, however, remain poorly characterized. We used a human ORFeome library to perform a high-throughput screen in mammalian cells and identified novel cytoplasmic signaling effector candidates including the Down syndrome kinase Dyrk1a, STAT3, USP21, and SH2D2A. Unexpectedly, we also found that the intracellular domains (ICDs) of DSCAM and DSCAML1 specifi...
Source: EMBO Journal - March 14, 2019 Category: Molecular Biology Authors: Sachse, S. M., Lievens, S., Ribeiro, L. F., Dascenco, D., Masschaele, D., Horre, K., Misbaer, A., Vanderroost, N., De Smet, A. S., Salta, E., Erfurth, M.-L., Kise, Y., Nebel, S., Van Delm, W., Plaisance, S., Tavernier, J., De Strooper, B., De Wit, J., Sch Tags: Neuroscience, Signal Transduction Articles Source Type: research
STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation
T helper 17 (Th17)-cell differentiation triggered by interleukin-6 (IL-6) via STAT3 activation promotes inflammation in inflammatory bowel disease (IBD) patients. However, leukemia inhibitory factor (LIF), an IL-6 family cytokine, restricts inflammation by blocking Th17-cell differentiation via an unknown mechanism. Here, we report that microbiota dysregulation promotes LIF secretion by intestinal epithelial cells (IECs) in a mouse colitis model. LIF greatly activates STAT4 phosphorylation on multiple SPXX elements within the C-terminal transcription regulation domain. STAT4 and STAT3 act reciprocally on both canonical cis...
Source: EMBO Journal - March 14, 2019 Category: Molecular Biology Authors: Zhang, Y. S., Xin, D. E., Wang, Z., Song, X., Sun, Y., Zou, Q. C., Yue, J., Zhang, C., Zhang, J. M., Liu, Z., Zhang, X., Zhao, T. C., Su, B., Chin, Y. E. Tags: Immunology, Signal Transduction Articles Source Type: research
