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Cell Reports

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https://www.readbyqxmd.com/read/27986592/the-fa-core-complex-contains-a-homo-dimeric-catalytic-module-for-the-symmetric-mono-ubiquitination-of-fanci-fancd2
#1
Paolo Swuec, Ludovic Renault, Aaron Borg, Fenil Shah, Vincent J Murphy, Sylvie van Twest, Bram Snijders, Andrew J Deans, Alessandro Costa
Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear...
December 9, 2016: Cell Reports
https://www.readbyqxmd.com/read/28076798/neonatal-transplantation-confers-maturation-of-psc-derived-cardiomyocytes-conducive-to-modeling-cardiomyopathy
#2
Gun-Sik Cho, Dong I Lee, Emmanouil Tampakakis, Sean Murphy, Peter Andersen, Hideki Uosaki, Stephen Chelko, Khalid Chakir, Ingie Hong, Kinya Seo, Huei-Sheng Vincent Chen, Xiongwen Chen, Cristina Basso, Steven R Houser, Gordon F Tomaselli, Brian O'Rourke, Daniel P Judge, David A Kass, Chulan Kwon
Pluripotent stem cells (PSCs) offer unprecedented opportunities for disease modeling and personalized medicine. However, PSC-derived cells exhibit fetal-like characteristics and remain immature in a dish. This has emerged as a major obstacle for their application for late-onset diseases. We previously showed that there is a neonatal arrest of long-term cultured PSC-derived cardiomyocytes (PSC-CMs). Here, we demonstrate that PSC-CMs mature into adult CMs when transplanted into neonatal hearts. PSC-CMs became similar to adult CMs in morphology, structure, and function within a month of transplantation into rats...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076797/major-shifts-in-glial-regional-identity-are-a-transcriptional-hallmark-of-human-brain-aging
#3
Lilach Soreq, Jamie Rose, Eyal Soreq, John Hardy, Daniah Trabzuni, Mark R Cookson, Colin Smith, Mina Ryten, Rickie Patani, Jernej Ule
Gene expression studies suggest that aging of the human brain is determined by a complex interplay of molecular events, although both its region- and cell-type-specific consequences remain poorly understood. Here, we extensively characterized aging-altered gene expression changes across ten human brain regions from 480 individuals ranging in age from 16 to 106 years. We show that astrocyte- and oligodendrocyte-specific genes, but not neuron-specific genes, shift their regional expression patterns upon aging, particularly in the hippocampus and substantia nigra, while the expression of microglia- and endothelial-specific genes increase in all brain regions...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076796/ribosomal-proteins-rpl22-and-rpl22l1-control-morphogenesis-by-regulating-pre-mrna-splicing
#4
Yong Zhang, Monique N O'Leary, Suraj Peri, Minshi Wang, Jikun Zha, Simon Melov, Dietmar J Kappes, Qing Feng, Jennifer Rhodes, Paul S Amieux, David R Morris, Brian K Kennedy, David L Wiest
Most ribosomal proteins (RP) are regarded as essential, static components that contribute only to ribosome biogenesis and protein synthesis. However, emerging evidence suggests that RNA-binding RP are dynamic and can influence cellular processes by performing "extraribosomal," regulatory functions involving binding to select critical target mRNAs. We report here that the RP, Rpl22, and its highly homologous paralog Rpl22-Like1 (Rpl22l1 or Like1) play critical, extraribosomal roles in embryogenesis. Indeed, they antagonistically control morphogenesis through developmentally regulated localization to the nucleus, where they modulate splicing of the pre-mRNA encoding smad2, an essential transcriptional effector of Nodal/TGF-β signaling...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076795/hangover-links-nuclear-rna-signaling-to-camp-regulation-via-the-phosphodiesterase-4d-ortholog-dunce
#5
Manuela Ruppert, Mirjam Franz, Anastasios Saratsis, Laura Velo Escarcena, Oliver Hendrich, Li Ming Gooi, Isabell Schwenkert, Ansgar Klebes, Henrike Scholz
The hangover gene defines a cellular stress pathway that is required for rapid ethanol tolerance in Drosophila melanogaster. To understand how cellular stress changes neuronal function, we analyzed Hangover function on a cellular and neuronal level. We provide evidence that Hangover acts as a nuclear RNA binding protein and we identified the phosphodiesterase 4d ortholog dunce as a target RNA. We generated a transcript-specific dunce mutant that is impaired not only in ethanol tolerance but also in the cellular stress response...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076794/brca1-directs-the-repair-pathway-to-homologous-recombination-by-promoting-53bp1-dephosphorylation
#6
Mayu Isono, Atsuko Niimi, Takahiro Oike, Yoshihiko Hagiwara, Hiro Sato, Ryota Sekine, Yukari Yoshida, Shin-Ya Isobe, Chikashi Obuse, Ryotaro Nishi, Elena Petricci, Shinichiro Nakada, Takashi Nakano, Atsushi Shibata
BRCA1 promotes homologous recombination (HR) by activating DNA-end resection. By contrast, 53BP1 forms a barrier that inhibits DNA-end resection. Here, we show that BRCA1 promotes DNA-end resection by relieving the 53BP1-dependent barrier. We show that 53BP1 is phosphorylated by ATM in S/G2 phase, promoting RIF1 recruitment, which inhibits resection. 53BP1 is promptly dephosphorylated and RIF1 released, despite remaining unrepaired DNA double-strand breaks (DSBs). When resection is impaired by CtIP/MRE11 endonuclease inhibition, 53BP1 phosphorylation and RIF1 are sustained due to ongoing ATM signaling...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076793/chloroquine-inducible-par-4-secretion-is-essential-for-tumor-cell-apoptosis-and-inhibition-of-metastasis
#7
Ravshan Burikhanov, Nikhil Hebbar, Sunil K Noothi, Nidhi Shukla, James Sledziona, Nathália Araujo, Meghana Kudrimoti, Qing Jun Wang, David S Watt, Danny R Welch, Jodi Maranchie, Akihiro Harada, Vivek M Rangnekar
The induction of tumor suppressor proteins capable of cancer cell apoptosis represents an attractive option for the re-purposing of existing drugs. We report that the anti-malarial drug, chloroquine (CQ), is a robust inducer of Par-4 secretion from normal cells in mice and cancer patients in a clinical trial. CQ-inducible Par-4 secretion triggers paracrine apoptosis of cancer cells and also inhibits metastatic tumor growth. CQ induces Par-4 secretion via the classical secretory pathway that requires the activation of p53...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076792/the-mre11-nbs1-interface-is-essential-for-viability-and-tumor-suppression
#8
Jun Hyun Kim, Malgorzata Grosbart, Roopesh Anand, Claire Wyman, Petr Cejka, John H J Petrini
The Mre11 complex (Mre11, Rad50, and Nbs1) is integral to both DNA repair and ataxia telangiectasia mutated (ATM)-dependent DNA damage signaling. All three Mre11 complex components are essential for viability at the cellular and organismal levels. To delineate essential and non-essential Mre11 complex functions that are mediated by Nbs1, we used TALEN-based genome editing to derive Nbs1 mutant mice (Nbs1(mid) mice), which harbor mutations in the Mre11 interaction domain of Nbs1. Nbs1(mid) alleles that abolished interaction were incompatible with viability...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076791/mll-af4-spreading-identifies-binding-sites-that-are-distinct-from-super-enhancers-and-that-govern-sensitivity-to-dot1l-inhibition-in-leukemia
#9
Jon Kerry, Laura Godfrey, Emmanouela Repapi, Marta Tapia, Neil P Blackledge, Helen Ma, Erica Ballabio, Sorcha O'Byrne, Frida Ponthan, Olaf Heidenreich, Anindita Roy, Irene Roberts, Marina Konopleva, Robert J Klose, Huimin Geng, Thomas A Milne
Understanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the mixed-lineage leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor-prognosis leukemias. Here, we find that at a subset of gene targets, MLL-AF4 binding spreads into the gene body and is associated with the spreading of Menin binding, increased transcription, increased H3K79 methylation (H3K79me2/3), a disruption of normal H3K36me3 patterns, and unmethylated CpG regions in the gene body...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076790/the-anti-warburg-effect-elicited-by-the-camp-pgc1%C3%AE-pathway-drives-differentiation-of-glioblastoma-cells-into-astrocytes
#10
Fan Xing, Yizhao Luan, Jing Cai, Sihan Wu, Jialuo Mai, Jiayu Gu, Haipeng Zhang, Kai Li, Yuan Lin, Xiao Xiao, Jiankai Liang, Yuan Li, Wenli Chen, Yaqian Tan, Longxiang Sheng, Bingzheng Lu, Wanjun Lu, Mingshi Gao, Pengxin Qiu, Xingwen Su, Wei Yin, Jun Hu, Zhongping Chen, Ke Sai, Jing Wang, Furong Chen, Yinsheng Chen, Shida Zhu, Dongbing Liu, Shiyuan Cheng, Zhi Xie, Wenbo Zhu, Guangmei Yan
Glioblastoma multiforme (GBM) is among the most aggressive of human cancers. Although differentiation therapy has been proposed as a potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established an induced differentiation model of GBM using cAMP activators that specifically directed GBM differentiation into astroglia. Transcriptomic and proteomic analyses revealed that oxidative phosphorylation and mitochondrial biogenesis are involved in induced differentiation of GBM...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076789/reduced-insulin-igf-1-signaling-restores-the-dynamic-properties-of-key-stress-granule-proteins-during-aging
#11
Marie C Lechler, Emily D Crawford, Nicole Groh, Katja Widmaier, Raimund Jung, Janine Kirstein, Jonathan C Trinidad, Alma L Burlingame, Della C David
Low-complexity "prion-like" domains in key RNA-binding proteins (RBPs) mediate the reversible assembly of RNA granules. Individual RBPs harboring these domains have been linked to specific neurodegenerative diseases. Although their aggregation in neurodegeneration has been extensively characterized, it remains unknown how the process of aging disturbs RBP dynamics. We show that a wide variety of RNA granule components, including stress granule proteins, become highly insoluble with age in C. elegans and that reduced insulin/insulin-like growth factor 1 (IGF-1) daf-2 receptor signaling efficiently prevents their aggregation...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076788/dynamin-2-stabilizes-the-hiv-1-fusion-pore-with-a-low-oligomeric-state
#12
Daniel M Jones, Luis A Alvarez, Rory Nolan, Margarita Ferriz, Raquel Sainz Urruela, Xènia Massana-Muñoz, Hila Novak-Kotzer, Michael L Dustin, Sergi Padilla-Parra
One of the key research areas surrounding HIV-1 concerns the regulation of the fusion event that occurs between the virus particle and the host cell during entry. Even if it is universally accepted that the large GTPase dynamin-2 is important during HIV-1 entry, its exact role during the first steps of HIV-1 infection is not well characterized. Here, we have utilized a multidisciplinary approach to study the DNM2 role during fusion of HIV-1 in primary resting CD4 T and TZM-bl cells. We have combined advanced light microscopy and functional cell-based assays to experimentally assess the role of dynamin-2 during these processes...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076787/impdh2-is-an-intracellular-target-of-the-cyclophilin-a-and-sanglifehrin-a-complex
#13
Khian Hong Pua, Dylan T Stiles, Mathew E Sowa, Gregory L Verdine
Natural products have demonstrated utility in the clinic and can also act as probes to understand complex cellular pathways. Sanglifehrin A (SFA) is a mixed polyketide and non-ribosomal peptide synthase natural product with sub-nano-molar affinity for its receptor cyclophilin A (PPIA). It has been shown to behave in vitro as an immune suppressant. Here, we identify inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) as an intracellular target of the PPIA-SFA binary complex. The formation of this ternary complex does not inhibit the enzymatic activity of IMPDH2...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076786/porphyromonas-gingivalis-promotes-unrestrained-type-i-interferon-production-by-dysregulating-tam-signaling-via-myd88-degradation
#14
Gabriel Mizraji, Maria Nassar, Hadas Segev, Hafiz Sharawi, Luba Eli-Berchoer, Tal Capucha, Tsipora Nir, Yaara Tabib, Avraham Maimon, Shira Dishon, Lior Shapira, Gabriel Nussbaum, Asaf Wilensky, Avi-Hai Hovav
Whereas type I interferons (IFNs-I) were proposed to be elevated in human periodontitis, their role in the disease remains elusive. Using a bacterial-induced model of murine periodontitis, we revealed a prolonged elevation in IFN-I expression. This was due to the downregulation of TAM signaling, a major negative regulator of IFN-I. Further examination revealed that the expression of certain TAM components was reduced as a result of prolonged degradation of MYD88 by the infection. As a result of such prolonged IFN-I production, innate immunological functions of the gingiva were disrupted, and CD4(+) T cells were constitutively primed by dendritic cells, leading to elevated RANKL expression and, subsequently, alveolar bone loss (ABL)...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076785/infection-programs-sustained-lymphoid-stromal-cell-responses-and-shapes-lymph-node-remodeling-upon-secondary-challenge
#15
Julia L Gregory, Anne Walter, Yannick O Alexandre, Jyh Liang Hor, Ruijie Liu, Joel Z Ma, Sapna Devi, Nobuko Tokuda, Yuji Owada, Laura K Mackay, Gordon K Smyth, William R Heath, Scott N Mueller
Lymph nodes (LNs) are constructed of intricate networks of endothelial and mesenchymal stromal cells. How these lymphoid stromal cells (LSCs) regulate lymphoid tissue remodeling and contribute to immune responses remains poorly understood. We performed a comprehensive functional and transcriptional analysis of LSC responses to skin viral infection and found that LSC subsets responded robustly, with different kinetics for distinct pathogens. Recruitment of cells to inflamed LNs induced LSC expansion, while B cells sustained stromal responses in an antigen-independent manner...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076784/coupled-proliferation-and-apoptosis-maintain-the-rapid-turnover-of-microglia-in-the-adult-brain
#16
Katharine Askew, Kaizhen Li, Adrian Olmos-Alonso, Fernando Garcia-Moreno, Yajie Liang, Philippa Richardson, Tom Tipton, Mark A Chapman, Kristoffer Riecken, Sol Beccari, Amanda Sierra, Zoltán Molnár, Mark S Cragg, Olga Garaschuk, V Hugh Perry, Diego Gomez-Nicola
Microglia play key roles in brain development, homeostasis, and function, and it is widely assumed that the adult population is long lived and maintained by self-renewal. However, the precise temporal and spatial dynamics of the microglial population are unknown. We show in mice and humans that the turnover of microglia is remarkably fast, allowing the whole population to be renewed several times during a lifetime. The number of microglial cells remains steady from late postnatal stages until aging and is maintained by the spatial and temporal coupling of proliferation and apoptosis, as shown by pulse-chase studies, chronic in vivo imaging of microglia, and the use of mouse models of dysregulated apoptosis...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076783/cdyl-deficiency-disrupts-neuronal-migration-and-increases-susceptibility-to-epilepsy
#17
Rui Qin, Shuai Cao, Tianjie Lyu, Cai Qi, Weiguang Zhang, Yun Wang
During brain development, the correct migration of newborn neurons is one of the determinants of circuit formation, and neuronal migration defects may lead to neurological and psychiatric disorders. The molecular mechanisms underlying neuronal migration and related disorders are poorly understood. Here, we report that Chromodomain Y-like (CDYL) is critical for neuronal migration in mice. Knocking down CDYL caused neuronal migration defects and disrupted both mobility and multipolar-to-bipolar transition of migrating neurons...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076782/gfr%C3%AE-1-regulates-purkinje-cell-migration-by-counteracting-ncam-function
#18
Maria Christina Sergaki, Carlos F Ibáñez
During embryonic development of the cerebellum, Purkinje cells (PCs) migrate away from the ventricular zone to form the PC plate. The mechanisms that regulate PC migration are incompletely understood. Here, we report that the neurotrophic receptor GFRα1 is transiently expressed in developing PCs and loss of GFRα1 delays PC migration. Neither GDNF nor RET, the canonical GFRα1 ligand and co-receptor, respectively, contribute to this process. Instead, we found that the neural cell adhesion molecule NCAM is co-expressed and directly interacts with GFRα1 in embryonic PCs...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076781/crtc1-nuclear-translocation-following-learning-modulates-memory-strength-via-exchange-of-chromatin-remodeling-complexes-on-the-fgf1-gene
#19
Shusaku Uchida, Brett J W Teubner, Charles Hevi, Kumiko Hara, Ayumi Kobayashi, Rutu M Dave, Tatsushi Shintaku, Pattaporn Jaikhan, Hirotaka Yamagata, Takayoshi Suzuki, Yoshifumi Watanabe, Stanislav S Zakharenko, Gleb P Shumyatsky
Memory is formed by synapse-to-nucleus communication that leads to regulation of gene transcription, but the identity and organizational logic of signaling pathways involved in this communication remain unclear. Here we find that the transcription cofactor CRTC1 is a critical determinant of sustained gene transcription and memory strength in the hippocampus. Following associative learning, synaptically localized CRTC1 is translocated to the nucleus and regulates Fgf1b transcription in an activity-dependent manner...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076780/det1-and-hy5-control-pif4-mediated-thermosensory-elongation-growth-through-distinct-mechanisms
#20
Sreeramaiah N Gangappa, S Vinod Kumar
Plant growth and development are defined by environmental cues. The transcription factor PHYTOCHROME INTERACTING FACTOR 4 (PIF4) is the central signaling hub that integrates environmental cues, including light and temperature, to regulate growth and development. The thermosensory mechanisms controlling the PIF4-mediated temperature response, and its integration with other environmental responses, remain poorly understood. DE-ETIOLATED 1 (DET1) and CONSTITUTIVE PHOTOMORPHOGENESIS 1 (COP1), key regulators of light signaling, have been proposed to control thermosensory growth by transcriptional regulation of PIF4, through ELONGATED HYPOCOTYL 5 (HY5)...
January 10, 2017: Cell Reports
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