7,318 results match your criteria Molecular Cell [Journal]


Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein's C-Terminal Helix.

Mol Cell 2019 Apr 5. Epub 2019 Apr 5.

Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address:

The cyclin-dependent kinases Cdk4 and Cdk6 form complexes with D-type cyclins to drive cell proliferation. A well-known target of cyclin D-Cdk4,6 is the retinoblastoma protein Rb, which inhibits cell-cycle progression until its inactivation by phosphorylation. However, the role of Rb phosphorylation by cyclin D-Cdk4,6 in cell-cycle progression is unclear because Rb can be phosphorylated by other cyclin-Cdks, and cyclin D-Cdk4,6 has other targets involved in cell division. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.020DOI Listing

Dual Role of Ribosome-Binding Domain of NAC as a Potent Suppressor of Protein Aggregation and Aging-Related Proteinopathies.

Mol Cell 2019 Apr 8. Epub 2019 Apr 8.

Department of Biology, University of Konstanz, 78457 Konstanz, Germany. Electronic address:

The nascent polypeptide-associated complex (NAC) is a conserved ribosome-associated protein biogenesis factor. Whether NAC exerts chaperone activity and whether this function is restricted to de novo protein synthesis is unknown. Here, we demonstrate that NAC directly exerts chaperone activity toward structurally diverse model substrates including polyglutamine (PolyQ) proteins, firefly luciferase, and Aβ40. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.012DOI Listing

An Adversarial DNA N-Methyladenine-Sensor Network Preserves Polycomb Silencing.

Mol Cell 2019 Apr 5. Epub 2019 Apr 5.

Department of Pathology, Keck School of Medicine of USC, Los Angeles, CA 90033, USA. Electronic address:

Adenine N6 methylation in DNA (6mA) is widespread among bacteria and phage and is detected in mammalian genomes, where its function is largely unexplored. Here we show that 6mA deposition and removal are catalyzed by the Mettl4 methyltransferase and Alkbh4 dioxygenase, respectively, and that 6mA accumulation in genic elements corresponds with transcriptional silencing. Inactivation of murine Mettl4 depletes 6mA and causes sublethality and craniofacial dysmorphism in incross progeny. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.018DOI Listing

C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function.

Mol Cell 2019 Apr 3. Epub 2019 Apr 3.

Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Sciences Center, Memphis, TN 38105, USA. Electronic address:

Repeat expansion in the C9orf72 gene is the most common cause of the neurodegenerative disorder amyotrophic lateral sclerosis (C9-ALS) and is linked to the unconventional translation of five dipeptide-repeat polypeptides (DPRs). The two enriched in arginine, poly(GR) and poly(PR), infiltrate liquid-like nucleoli, co-localize with the nucleolar protein nucleophosmin (NPM1), and alter the phase separation behavior of NPM1 in vitro. Here, we show that poly(PR) DPRs bind tightly to a long acidic tract within the intrinsically disordered region of NPM1, altering its phase separation with nucleolar partners to the extreme of forming large, soluble complexes that cause droplet dissolution in vitro. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.019DOI Listing
April 2019
1 Read

Structural Basis of Dot1L Stimulation by Histone H2B Lysine 120 Ubiquitination.

Mol Cell 2019 Apr 8. Epub 2019 Apr 8.

Skirball Institute of Biomolecular Medicine, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA. Electronic address:

The essential histone H3 lysine 79 methyltransferase Dot1L regulates transcription and genomic stability and is deregulated in leukemia. The activity of Dot1L is stimulated by mono-ubiquitination of histone H2B on lysine 120 (H2BK120Ub); however, the detailed mechanism is not understood. We report cryo-EM structures of human Dot1L bound to (1) H2BK120Ub and (2) unmodified nucleosome substrates at 3. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10972765193023
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http://dx.doi.org/10.1016/j.molcel.2019.03.029DOI Listing
April 2019
1 Read

ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97.

Mol Cell 2019 Apr 3. Epub 2019 Apr 3.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43-positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.027DOI Listing

Structural and Functional Insights into Host Death Domains Inactivation by the Bacterial Arginine GlcNAcyltransferase Effector.

Mol Cell 2019 Apr 3. Epub 2019 Apr 3.

National Institute of Biological Sciences, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China. Electronic address:

Enteropathogenic E. coli NleB and related type III effectors catalyze arginine GlcNAcylation of death domain (DD) proteins to block host defense, but the underlying mechanism is unknown. Here we solve crystal structures of NleB alone and in complex with FADD-DD, UDP, and Mn as well as NleB-GlcNAcylated DDs of TRADD and RIPK1. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.028DOI Listing

RRM Transcription Factors Interact with NLRs and Regulate Broad-Spectrum Blast Resistance in Rice.

Mol Cell 2019 Mar 23. Epub 2019 Mar 23.

National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology & Ecology, Chinese Academy of Sciences, Shanghai, China; College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China. Electronic address:

Nucleotide-binding site leucine-rich repeat (NLR) receptors perceive pathogen effectors and trigger plant immunity. However, the mechanisms underlying NLR-triggered defense responses remain obscure. The recently discovered Pigm locus in rice encodes a cluster of NLRs, including PigmR, which confers broad-spectrum resistance to blast fungus. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.013DOI Listing

Introducing a Spectrum of Long-Range Genomic Deletions in Human Embryonic Stem Cells Using Type I CRISPR-Cas.

Mol Cell 2019 Apr 5. Epub 2019 Apr 5.

Department of Biological Chemistry, University of Michigan, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address:

CRISPR-Cas systems enable microbial adaptive immunity and provide eukaryotic genome editing tools. These tools employ a single effector enzyme of type II or V CRISPR to generate RNA-guided, precise genome breaks. Here we demonstrate the feasibility of using type I CRISPR-Cas to effectively introduce a spectrum of long-range chromosomal deletions with a single RNA guide in human embryonic stem cells and HAP1 cells. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.014DOI Listing

The Landscape of L1 Retrotransposons in the Human Genome Is Shaped by Pre-insertion Sequence Biases and Post-insertion Selection.

Mol Cell 2019 Mar 29. Epub 2019 Mar 29.

Université Côte d'Azur, Inserm, CNRS, IRCAN, Nice, France. Electronic address:

L1 retrotransposons are transposable elements and major contributors of genetic variation in humans. Where L1 integrates into the genome can directly impact human evolution and disease. Here, we experimentally induced L1 retrotransposition in cells and mapped integration sites at nucleotide resolution. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.036DOI Listing

A Combined Approach Reveals a Regulatory Mechanism Coupling Src's Kinase Activity, Localization, and Phosphotransferase-Independent Functions.

Mol Cell 2019 Mar 25. Epub 2019 Mar 25.

Department of Chemistry, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Electronic address:

Multiple layers of regulation modulate the activity and localization of protein kinases. However, many details of kinase regulation remain incompletely understood. Here, we apply saturation mutagenesis and a chemical genetic method for allosterically modulating kinase global conformation to Src kinase, providing insight into known regulatory mechanisms and revealing a previously undiscovered interaction between Src's SH4 and catalytic domains. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.003DOI Listing
March 2019
1 Read

The Phospho-Code Determining Circadian Feedback Loop Closure and Output in Neurospora.

Mol Cell 2019 Mar 26. Epub 2019 Mar 26.

Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. Electronic address:

In the negative feedback loop driving fungal and animal circadian oscillators, negative elements (FREQUENCY [FRQ], PERIODS [PERs], and CRYPTOCHROMES [CRYs]) are understood to inhibit their own expression, in part by promoting the phosphorylation of their heterodimeric transcriptional activators (e.g., White Collar-1 [WC-1]-WC-2 [White Collar complex; WCC] and BMAL1/Circadian Locomotor Output Cycles Kaput [CLOCK]). Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.003DOI Listing
March 2019
3 Reads

DNA Damage Signaling-Induced Cancer Cell Reprogramming as a Driver of Tumor Relapse.

Mol Cell 2019 Mar 28. Epub 2019 Mar 28.

Institute for Research on Cancer and Aging of Nice (IRCAN), INSERM, Université Côte d'Azur, CNRS, Nice, France; Centre Antoine Lacassagne, Nice, France. Electronic address:

Accumulating evidence supports the role of the DNA damage response (DDR) in the negative regulation of tumorigenesis. Here, we found that DDR signaling poises a series of epigenetic events, resulting in activation of pro-tumorigenic genes but can go as far as reactivation of the pluripotency gene OCT4. Loss of DNA methylation appears to be a key initiating event in DDR-dependent OCT4 locus reactivation although full reactivation required the presence of a driving oncogene, such as Myc and macroH2A downregulation. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.002DOI Listing

Interleukin-1β Induces mtDNA Release to Activate Innate Immune Signaling via cGAS-STING.

Mol Cell 2019 Mar 22. Epub 2019 Mar 22.

Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA. Electronic address:

Interleukin-1 beta (IL-1β) is a pleiotropic mediator of inflammation and is produced in response to a wide range of stimuli. During infection, IL-1β production occurs in parallel with the onset of innate antimicrobial defenses, but the contribution of IL-1β signaling to cell-intrinsic immunity is not defined. Here, we report that exogenous IL-1β induces interferon regulatory factor 3 (IRF3) activation in human myeloid, fibroblast, and epithelial cells. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.038DOI Listing
March 2019
1 Read

Dynamic Recruitment of Single RNAs to Processing Bodies Depends on RNA Functionality.

Mol Cell 2019 Mar 23. Epub 2019 Mar 23.

Single Molecule Analysis Group, Department of Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA. Electronic address:

Cellular RNAs often colocalize with cytoplasmic, membrane-less ribonucleoprotein (RNP) granules enriched for RNA-processing enzymes, termed processing bodies (PBs). Here we track the dynamic localization of individual miRNAs, mRNAs, and long non-coding RNAs (lncRNAs) to PBs using intracellular single-molecule fluorescence microscopy. We find that unused miRNAs stably bind to PBs, whereas functional miRNAs, repressed mRNAs, and lncRNAs both transiently and stably localize within either the core or periphery of PBs, albeit to different extents. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10972765193017
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http://dx.doi.org/10.1016/j.molcel.2019.03.001DOI Listing
March 2019
3 Reads

Molecular Mechanisms Directing PRC2 Recruitment and H3K27 Methylation.

Mol Cell 2019 Apr;74(1):8-18

Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark; The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark; Cell Biology Program and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY 10065, USA. Electronic address:

The polycomb repressive complex 2 (PRC2) is a chromatin-associated methyltransferase catalyzing mono-, di-, and trimethylation of lysine 27 on histone H3 (H3K27). This activity is required for normal organismal development and maintenance of gene expression patterns to uphold cell identity. PRC2 function is often deregulated in disease and is a promising candidate for therapeutic targeting in cancer. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452890PMC
April 2019
1 Read

Beyond the Four Bases: A Home Run for Synthetic Epigenetic Control?

Mol Cell 2019 Apr;74(1):5-7

Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA. Electronic address:

Park et al. (2019) create a synthetic self-propagating adenine methylation system for epigenetic control in human cells. Targeting adenine allows their modular system to act orthogonally to most epigenetic processes, thereby opening the door for novel methods of controlling gene expression. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.016DOI Listing

Structure and Function in Drosophila Chromosomes: Visualizing Topological Domains.

Authors:
Daniel R Larson

Mol Cell 2019 Apr;74(1):3-4

Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address:

Cardozo Gizzi et al. (2019) develop a new sequential imaging methodology (Hi-M) for observing chromosome structure in the Drosophila blastoderm and find that topological domains in single nuclei change in response to transcriptional activation. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.017DOI Listing
April 2019
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Molecular Basis of Phage Communication.

Mol Cell 2019 Apr;74(1):1-2

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Recently members of Bacillus phages were found to utilize a small peptide (6 aa long) to communicate with their descendants, aiding in a complex decision-making process. Proteins involved in this remarkable viral communication phenomenon were further investigated at the structural level for better understanding in this issue of Molecular Cell (Gallego del Sol et al., 2019). Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.015DOI Listing

Gamblers: An Antibiotic-Induced Evolvable Cell Subpopulation Differentiated by Reactive-Oxygen-Induced General Stress Response.

Mol Cell 2019 Mar 26. Epub 2019 Mar 26.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA; The Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry and Cell Biology, Rice University, Houston, TX 77030, USA; Systems, Synthetic, and Physical Biology Program, Rice University, Houston, TX 77030, USA. Electronic address:

Antibiotics can induce mutations that cause antibiotic resistance. Yet, despite their importance, mechanisms of antibiotic-promoted mutagenesis remain elusive. We report that the fluoroquinolone antibiotic ciprofloxacin (cipro) induces mutations by triggering transient differentiation of a mutant-generating cell subpopulation, using reactive oxygen species (ROS). Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.037DOI Listing
March 2019
1 Read

Gain of Additional BIRC3 Protein Functions through 3'-UTR-Mediated Protein Complex Formation.

Mol Cell 2019 Apr 1. Epub 2019 Apr 1.

Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Alternative 3' untranslated regions (3' UTRs) are widespread, but their functional roles are largely unknown. We investigated the function of the long BIRC3 3' UTR, which is upregulated in leukemia. The 3' UTR does not regulate BIRC3 protein localization or abundance but is required for CXCR4-mediated B cell migration. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.006DOI Listing

Disruption of Telomerase RNA Maturation Kinetics Precipitates Disease.

Mol Cell 2019 Mar 28. Epub 2019 Mar 28.

Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Mutations in RNA-processing enzymes are increasingly linked to human disease. Telomerase RNA and related noncoding RNAs require 3' end-processing steps, including oligoadenylation. Germline mutations in poly(A)ribonuclease (PARN) cause accumulation of extended human telomerase RNA (hTR) species and precipitate dyskeratosis congenita and pulmonary fibrosis. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.033DOI Listing
March 2019
1 Read

TOP2β-Dependent Nuclear DNA Damage Shapes Extracellular Growth Factor Responses via Dynamic AKT Phosphorylation to Control Virus Latency.

Mol Cell 2019 Mar 26. Epub 2019 Mar 26.

Department of Biochemistry & Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Institute, NYU School of Medicine, New York, NY 10016, USA. Electronic address:

The mTOR pathway integrates both extracellular and intracellular signals and serves as a central regulator of cell metabolism, growth, survival, and stress responses. Neurotropic viruses, such as herpes simplex virus-1 (HSV-1), also rely on cellular AKT-mTORC1 signaling to achieve viral latency. Here, we define a novel genotoxic response whereby spatially separated signals initiated by extracellular neurotrophic factors and nuclear DNA damage are integrated by the AKT-mTORC1 pathway. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.032DOI Listing
March 2019
2 Reads

Endoribonucleolytic Cleavage of mA-Containing RNAs by RNase P/MRP Complex.

Mol Cell 2019 Mar 22. Epub 2019 Mar 22.

Creative Research Initiatives Center for Molecular Biology of Translation, Korea University, Seoul 02841, Republic of Korea; Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea. Electronic address:

N-methyladenosine (mA) is the most abundant internal modification in RNAs and plays regulatory roles in a variety of biological and physiological processes. Despite its important roles, the molecular mechanism underlying mA-mediated gene regulation is poorly understood. Here, we show that mA-containing RNAs are subject to endoribonucleolytic cleavage via YTHDF2 (mA reader protein), HRSP12 (adaptor protein), and RNase P/MRP (endoribonucleases). Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.034DOI Listing
March 2019
1 Read

MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation.

Mol Cell 2019 Mar 21. Epub 2019 Mar 21.

Cancer Systems Biology Group, Theodor Boveri Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany. Electronic address:

The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.031DOI Listing
March 2019
2 Reads

Differential Oligomerization of the Deubiquitinases USP25 and USP28 Regulates Their Activities.

Mol Cell 2019 Mar 22. Epub 2019 Mar 22.

Rudolf Virchow Center for Experimental Biomedicine, Institute for Structural Biology, University of Würzburg, 97080 Würzburg, Germany; Comprehensive Cancer Center Mainfranken, 97080 Würzburg, Germany. Electronic address:

Deubiquitinases have emerged as promising drug targets for cancer therapy. The two DUBs USP25 and USP28 share high similarity but vary in their cellular functions. USP28 is known for its tumor-promoting role, whereas USP25 is a regulator of the innate immune system and, recently, a role in tumorigenesis was proposed. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.029DOI Listing

Distinct USP25 and USP28 Oligomerization States Regulate Deubiquitinating Activity.

Mol Cell 2019 Mar 21. Epub 2019 Mar 21.

Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia. Electronic address:

The evolutionarily related deubiquitinating enzymes (DUBs) USP25 and USP28 comprise an identical overall domain architecture but are functionally non-redundant: USP28 stabilizes c-MYC and other nuclear proteins, and USP25 regulates inflammatory TRAF signaling. We here compare molecular features of USP25 and USP28. Active enzymes form distinctively shaped dimers, with a dimerizing insertion spatially separating independently active catalytic domains. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.030DOI Listing

A Role for Chromatin Remodeling in Cohesin Loading onto Chromosomes.

Mol Cell 2019 Mar 22. Epub 2019 Mar 22.

Chromosome Segregation Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address:

Cohesin is a conserved, ring-shaped protein complex that topologically embraces DNA. Its central role in genome organization includes functions in sister chromatid cohesion, DNA repair, and transcriptional regulation. Cohesin loading onto chromosomes requires the Scc2-Scc4 cohesin loader, whose presence on chromatin in budding yeast depends on the RSC chromatin remodeling complex. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.027DOI Listing

High-Dimensional Single-Cell Cartography Reveals Novel Skeletal Muscle-Resident Cell Populations.

Mol Cell 2019 Mar 22. Epub 2019 Mar 22.

Sorbonne Université, INSERM UMRS974, Association Institut de Myologie, Centre de Recherche en Myologie, 75013 Paris, France. Electronic address:

Adult tissue repair and regeneration require stem-progenitor cells that can self-renew and generate differentiated progeny. Skeletal muscle regenerative capacity relies on muscle satellite cells (MuSCs) and their interplay with different cell types within the niche. However, our understanding of skeletal muscle tissue cellular composition is limited. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.026DOI Listing

Extensive Recovery of Embryonic Enhancer and Gene Memory Stored in Hypomethylated Enhancer DNA.

Mol Cell 2019 Mar 15. Epub 2019 Mar 15.

Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address:

Developing and adult tissues use different cis-regulatory elements. Although DNA at some decommissioned embryonic enhancers is hypomethylated in adult cells, it is unknown whether this putative epigenetic memory is complete and recoverable. We find that, in adult mouse cells, hypomethylated CpG dinucleotides preserve a nearly complete archive of tissue-specific developmental enhancers. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.024DOI Listing
March 2019
14.018 Impact Factor

Cut-and-Run: A Distinct Mechanism by which V(D)J Recombination Causes Genome Instability.

Mol Cell 2019 Mar 18. Epub 2019 Mar 18.

School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK. Electronic address:

V(D)J recombination is essential to generate antigen receptor diversity but is also a potent cause of genome instability. Many chromosome alterations that result from aberrant V(D)J recombination involve breaks at single recombination signal sequences (RSSs). A long-standing question, however, is how such breaks occur. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.025DOI Listing
March 2019
1 Read
14.018 Impact Factor

Retapamulin-Assisted Ribosome Profiling Reveals the Alternative Bacterial Proteome.

Mol Cell 2019 Mar 8. Epub 2019 Mar 8.

Center for Biomolecular Sciences-m/c 870, University of Illinois at Chicago, 900 S. Ashland Ave., Chicago, IL 60607, USA. Electronic address:

The use of alternative translation initiation sites enables production of more than one protein from a single gene, thereby expanding the cellular proteome. Although several such examples have been serendipitously found in bacteria, genome-wide mapping of alternative translation start sites has been unattainable. We found that the antibiotic retapamulin specifically arrests initiating ribosomes at start codons of the genes. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.017DOI Listing

Protein Kinase C Quality Control by Phosphatase PHLPP1 Unveils Loss-of-Function Mechanism in Cancer.

Mol Cell 2019 Mar 20. Epub 2019 Mar 20.

Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address:

Protein kinase C (PKC) isozymes function as tumor suppressors in increasing contexts. In contrast to oncogenic kinases, whose function is acutely regulated by transient phosphorylation, PKC is constitutively phosphorylated following biosynthesis to yield a stable, autoinhibited enzyme that is reversibly activated by second messengers. Here, we report that the phosphatase PHLPP1 opposes PKC phosphorylation during maturation, leading to the degradation of aberrantly active species that do not become autoinhibited. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.018DOI Listing

RNA Circularization Diminishes Immunogenicity and Can Extend Translation Duration In Vivo.

Mol Cell 2019 Mar 19. Epub 2019 Mar 19.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address:

Circular RNAs (circRNAs) are a class of single-stranded RNAs with a contiguous structure that have enhanced stability and a lack of end motifs necessary for interaction with various cellular proteins. Here, we show that unmodified exogenous circRNA is able to bypass cellular RNA sensors and thereby avoid provoking an immune response in RIG-I and Toll-like receptor (TLR) competent cells and in mice. The immunogenicity and protein expression stability of circRNA preparations are found to be dependent on purity, with small amounts of contaminating linear RNA leading to robust cellular immune responses. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10972765193010
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http://dx.doi.org/10.1016/j.molcel.2019.02.015DOI Listing
March 2019
7 Reads

Gene-Specific H1 Eviction through a Transcriptional Activator→p300→NAP1→H1 Pathway.

Mol Cell 2019 Mar 15. Epub 2019 Mar 15.

Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA. Electronic address:

Linker histone H1 has been correlated with transcriptional inhibition, but the mechanistic basis of the inhibition and its reversal during gene activation has remained enigmatic. We report that H1-compacted chromatin, reconstituted in vitro, blocks transcription by abrogating core histone modifications by p300 but not activator and p300 binding. Transcription from H1-bound chromatin is elicited by the H1 chaperone NAP1, which is recruited in a gene-specific manner through direct interactions with activator-bound p300 that facilitate core histone acetylation (by p300) and concomitant eviction of H1 and H2A-H2B. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.016DOI Listing

MST1 Negatively Regulates TNFα-Induced NF-κB Signaling through Modulating LUBAC Activity.

Mol Cell 2019 Mar 21;73(6):1138-1149.e6. Epub 2019 Feb 21.

Department of Life Sciences, Korea University, Seoul 02841, South Korea. Electronic address:

The nuclear factor (NF)-κB pathway plays a central role in inflammatory and immune responses, with aberrant activation of NF-κB signaling being implicated in various human disorders. Here, we show that mammalian ste20-like kinase 1 (MST1) is a previously unrecognized component of the tumor necrosis factor α (TNFα) receptor 1 signaling complex (TNF-RSC) and attenuates TNFα-induced NF-κB signaling. Genetic ablation of MST1 in mouse embryonic fibroblasts and bone marrow-derived macrophages potentiated the TNFα-induced increase in IκB kinase (IKK) activity, as well as the expression of NF-κB target genes. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.022DOI Listing

Craving for Introns.

Mol Cell 2019 Mar;73(6):1095-1096

Department of Biology, Brandeis University, 415 South Street, Waltham, MA 02453, USA. Electronic address:

Parenteau et al. (2019) and Morgan et al. (2019) showed that a subset of introns can work as non-coding RNAs that trap the spliceosome and decrease global splicing upon nutrient depletion in yeast, providing a new example of the functionality of introns, molecules that were previously assumed to be useless. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.008DOI Listing
March 2019
1 Read

TARGET-seq Takes Aim at Cancer Evolution through Multi-omics Single-Cell Genotyping and Transcriptomics.

Mol Cell 2019 Mar;73(6):1092-1094

Division of Hematology and Medical Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; New York Genome Center, New York, NY, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA. Electronic address:

In this issue of Molecular Cell, Rodriguez-Meira et al. (2019) present TARGET-seq, an elegant single-cell method that genotypes somatic mutations and captures whole transcriptomes in the same tumor cells, thus paving the way to directly link somatic mutations with resulting transcriptional phenotypes in clonally diverse cancer populations. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.009DOI Listing

Context Matters: RNF168 Connects with PALB2 to Rewire Homologous Recombination in BRCA1 Haploinsufficiency.

Mol Cell 2019 Mar;73(6):1089-1091

Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address:

In this issue of Molecular Cell, Zong et al. (2019) reveal RNF168-driven chromatin ubiquitylation as a key back-up mechanism to sustain homologous recombination (HR) independently of BRCA1. These findings provide new clues to carcinogenesis and cancer therapy in BRCA1 heterozygous mutation carriers. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.005DOI Listing

The Long and the Short of the RNA Polymerase C-Terminal Domain and Phase Separation.

Mol Cell 2019 Mar;73(6):1087-1088

Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

In this issue of Molecular Cell, Lu et al. (2019) analyze the role of the length and sequence complexity of the RNA polymerase II unstructured C-terminal domain in animal viability, development, and the dynamics of RNA polymerase II in vivo. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.03.004DOI Listing

Inheritance of a Phenotypically Neutral Epimutation Evokes Gene Silencing in Later Generations.

Mol Cell 2019 Mar 5. Epub 2019 Mar 5.

Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland; University of Basel, Petersplatz 10, 4003 Basel, Switzerland. Electronic address:

Small RNAs trigger the formation of epialleles that are silenced across generations. Consequently, RNA-directed epimutagenesis is associated with persistent gene repression. Here, we demonstrate that small interfering RNA-induced epimutations in fission yeast are still inherited even when the silenced gene is reactivated, and descendants can reinstate the silencing phenotype that only occurred in their ancestors. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.009DOI Listing
March 2019
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MDC1 Interacts with TOPBP1 to Maintain Chromosomal Stability during Mitosis.

Mol Cell 2019 Mar 18. Epub 2019 Mar 18.

Department of Gynecology, University Hospital and University of Zurich, Wagistrasse 14, 8952 Schlieren, Switzerland. Electronic address:

In mitosis, cells inactivate DNA double-strand break (DSB) repair pathways to preserve genome stability. However, some early signaling events still occur, such as recruitment of the scaffold protein MDC1 to phosphorylated histone H2AX at DSBs. Yet, it remains unclear whether these events are important for maintaining genome stability during mitosis. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.014DOI Listing
March 2019
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MDM2 Integrates Cellular Respiration and Apoptotic Signaling through NDUFS1 and the Mitochondrial Network.

Mol Cell 2019 Mar 9. Epub 2019 Mar 9.

Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; The Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address:

Signaling diversity and subsequent complexity in higher eukaryotes is partially explained by one gene encoding a polypeptide with multiple biochemical functions in different cellular contexts. For example, mouse double minute 2 (MDM2) is functionally characterized as both an oncogene and a tumor suppressor, yet this dual classification confounds the cell biology and clinical literatures. Identified via complementary biochemical, organellar, and cellular approaches, we report that MDM2 negatively regulates NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1), leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.012DOI Listing

LC Domain-Mediated Coalescence Is Essential for Otu Enzymatic Activity to Extend Drosophila Lifespan.

Mol Cell 2019 Mar 11. Epub 2019 Mar 11.

State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing, 100101, China; School of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

In eukaryotic cells, RNA-binding proteins (RBPs) interact with RNAs to form ribonucleoprotein complexes (RNA granules) that have long been thought to regulate RNA fate or activity. Emerging evidence suggests that some RBPs not only bind RNA but also possess enzymatic activity related to ubiquitin regulation, raising important questions of whether these RBP-formed RNA granules regulate ubiquitin signaling and related biological functions. Here, we show that Drosophila Otu binds RNAs and coalesces to membrane-less biomolecular condensates via its intrinsically disordered low-complexity domain, and coalescence represents a functional state for Otu exerting deubiquitinase activity. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.004DOI Listing
March 2019
14.018 Impact Factor

Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3.

Mol Cell 2019 Apr 13;74(1):19-31.e7. Epub 2019 Mar 13.

Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Beijing 100871, China; Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Beijing 100044, China. Electronic address:

Viral infection triggers host defenses through pattern-recognition receptor-mediated cytokine production, inflammasome activation, and apoptosis of the infected cells. Inflammasome-activated caspases are known to cleave cyclic GMP-AMP synthase (cGAS). Here, we found that apoptotic caspases are critically involved in regulating both DNA and RNA virus-triggered host defenses, in which activated caspase-3 cleaved cGAS, MAVS, and IRF3 to prevent cytokine overproduction. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.013DOI Listing
April 2019
3 Reads

Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases.

Mol Cell 2019 Mar 13;73(6):1097-1114. Epub 2019 Mar 13.

Department of Biomedicine, University of Bergen, 5020 Bergen, Norway; Department of Biological Sciences, University of Bergen, 5020 Bergen, Norway; Department of Surgery, Haukeland University Hospital, 5021 Bergen, Norway. Electronic address:

Recent studies of N-terminal acetylation have identified new N-terminal acetyltransferases (NATs) and expanded the known functions of these enzymes beyond their roles as ribosome-associated co-translational modifiers. For instance, the identification of Golgi- and chloroplast-associated NATs shows that acetylation of N termini also happens post-translationally. In addition, we now appreciate that some NATs are highly specific; for example, a dedicated NAT responsible for post-translational N-terminal acetylation of actin was recently revealed. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.007DOI Listing

The Co-chaperone Cns1 and the Recruiter Protein Hgh1 Link Hsp90 to Translation Elongation via Chaperoning Elongation Factor 2.

Mol Cell 2019 Apr 12;74(1):73-87.e8. Epub 2019 Mar 12.

Center for Integrated Protein Science at the Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85748 Garching, Germany. Electronic address:

The Hsp90 chaperone machinery in eukaryotes comprises a number of distinct accessory factors. Cns1 is one of the few essential co-chaperones in yeast, but its structure and function remained unknown. Here, we report the X-ray structure of the Cns1 fold and NMR studies on the partly disordered, essential segment of the protein. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.011DOI Listing

Chaperone Function of Hgh1 in the Biogenesis of Eukaryotic Elongation Factor 2.

Mol Cell 2019 Apr 12;74(1):88-100.e9. Epub 2019 Mar 12.

Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany. Electronic address:

Eukaryotic elongation factor 2 (eEF2) is an abundant and essential component of the translation machinery. The biogenesis of this 93 kDa multi-domain protein is assisted by the chaperonin TRiC/CCT. Here, we show in yeast cells that the highly conserved protein Hgh1 (FAM203 in humans) is a chaperone that cooperates with TRiC in eEF2 folding. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.034DOI Listing
April 2019
6 Reads

Structure Reveals a Mechanism of CRISPR-RNA-Guided Nuclease Recruitment and Anti-CRISPR Viral Mimicry.

Mol Cell 2019 Apr 11;74(1):132-142.e5. Epub 2019 Mar 11.

Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA. Electronic address:

Bacteria and archaea have evolved sophisticated adaptive immune systems that rely on CRISPR RNA (crRNA)-guided detection and nuclease-mediated elimination of invading nucleic acids. Here, we present the cryo-electron microscopy (cryo-EM) structure of the type I-F crRNA-guided surveillance complex (Csy complex) from Pseudomonas aeruginosa bound to a double-stranded DNA target. Comparison of this structure to previously determined structures of this complex reveals a ∼180-degree rotation of the C-terminal helical bundle on the "large" Cas8f subunit. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.02.001DOI Listing