7,235 results match your criteria Molecular Cell [Journal]


Histone Acetyltransferase p300 Induces De Novo Super-Enhancers to Drive Cellular Senescence.

Mol Cell 2019 Feb 8. Epub 2019 Feb 8.

Epigenetics Institute, Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Accumulation of senescent cells during aging contributes to chronic inflammation and age-related diseases. While senescence is associated with profound alterations of the epigenome, a systematic view of epigenetic factors in regulating senescence is lacking. Here, we curated a library of short hairpin RNAs for targeted silencing of all known epigenetic proteins and performed a high-throughput screen to identify key candidates whose downregulation can delay replicative senescence of primary human cells. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.021DOI Listing
February 2019

Demethylation of the Protein Phosphatase PP2A Promotes Demethylation of Histones to Enable Their Function as a Methyl Group Sink.

Mol Cell 2019 Feb 1. Epub 2019 Feb 1.

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA. Electronic address:

Dysregulation of chromatin methylation is associated with defects in cellular differentiation as well as a variety of cancers. How cells regulate the opposing activities of histone methyltransferase and demethylase enzymes to set the methylation status of the epigenome for proper control of gene expression and metabolism remains poorly understood. Here, we show that loss of methylation of the major phosphatase PP2A in response to methionine starvation activates the demethylation of histones through hyperphosphorylation of specific demethylase enzymes. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.012DOI Listing
February 2019

PINK1 Inhibits Local Protein Synthesis to Limit Transmission of Deleterious Mitochondrial DNA Mutations.

Mol Cell 2019 Feb 1. Epub 2019 Feb 1.

National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

We have previously proposed that selective inheritance, the limited transmission of damaging mtDNA mutations from mother to offspring, is based on replication competition in Drosophila melanogaster. This model, which stems from our observation that wild-type mitochondria propagate much more vigorously in the fly ovary than mitochondria carrying fitness-impairing mutations, implies that germ cells recognize the fitness of individual mitochondria and selectively boost the propagation of healthy ones. Here, we demonstrate that the protein kinase PINK1 preferentially accumulates on mitochondria enriched for a deleterious mtDNA mutation. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.013DOI Listing
February 2019
2 Reads

Resolving Cell Fate Decisions during Somatic Cell Reprogramming by Single-Cell RNA-Seq.

Mol Cell 2019 Feb 13. Epub 2019 Feb 13.

CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou 510530, China; Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 511436, China; University of Chinese Academy of Sciences, Beijing 100049, China; Guangzhou Regenerative Medicine and Health GuangDong Laboratory (GRMH-GDL), Guangzhou 510005, China. Electronic address:

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs), which is a highly heterogeneous process. Here we report the cell fate continuum during somatic cell reprogramming at single-cell resolution. We first develop SOT to analyze cell fate continuum from Oct4/Sox2/Klf4- or OSK-mediated reprogramming and show that cells bifurcate into two categories, reprogramming potential (RP) or non-reprogramming (NR). Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.042DOI Listing
February 2019

The RNase PARN Controls the Levels of Specific miRNAs that Contribute to p53 Regulation.

Mol Cell 2019 Feb 8. Epub 2019 Feb 8.

Department of Biochemistry, University of Colorado, Boulder, CO 80303, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address:

PARN loss-of-function mutations cause a severe form of the hereditary disease dyskeratosis congenita (DC). PARN deficiency affects the stability of non-coding RNAs such as human telomerase RNA (hTR), but these effects do not explain the severe disease in patients. We demonstrate that PARN deficiency affects the levels of numerous miRNAs in human cells. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.010DOI Listing
February 2019

Nucleosomes Stabilize ssRNA-dsDNA Triple Helices in Human Cells.

Mol Cell 2019 Feb 8. Epub 2019 Feb 8.

Biochemistry Centre Regensburg (BCR), Universität Regensburg, 93053 Regensburg, Germany. Electronic address:

Chromatin-associated non-coding RNAs modulate the epigenetic landscape and its associated gene expression program. The formation of triple helices is one mechanism of sequence-specific targeting of RNA to chromatin. With this study, we show an important role of the nucleosome and its relative positioning to the triplex targeting site (TTS) in stabilizing RNA-DNA triplexes in vitro and in vivo. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.007DOI Listing
February 2019

The C-Terminal Domain of RNA Polymerase II Is a Multivalent Targeting Sequence that Supports Drosophila Development with Only Consensus Heptads.

Mol Cell 2019 Feb 1. Epub 2019 Feb 1.

Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA; The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA. Electronic address:

The C-terminal domain (CTD) of RNA polymerase II (Pol II) is composed of repeats of the consensus YSPTSPS and is an essential binding scaffold for transcription-associated factors. Metazoan CTDs have well-conserved lengths and sequence compositions arising from the evolution of divergent motifs, features thought to be essential for development. On the contrary, we show that a truncated CTD composed solely of YSPTSPS repeats supports Drosophila viability but that a CTD with enough YSPTSPS repeats to match the length of the wild-type Drosophila CTD is defective. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.008DOI Listing
February 2019

Unravelling Intratumoral Heterogeneity through High-Sensitivity Single-Cell Mutational Analysis and Parallel RNA Sequencing.

Mol Cell 2019 Feb 12. Epub 2019 Feb 12.

Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; National Institute for Health Research Biomedical Research Centre, University of Oxford, Oxford, UK. Electronic address:

Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for resolving transcriptional heterogeneity. However, its application to studying cancerous tissues is currently hampered by the lack of coverage across key mutation hotspots in the vast majority of cells; this lack of coverage prevents the correlation of genetic and transcriptional readouts from the same single cell. To overcome this, we developed TARGET-seq, a method for the high-sensitivity detection of multiple mutations within single cells from both genomic and coding DNA, in parallel with unbiased whole-transcriptome analysis. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.009DOI Listing
February 2019

Deciphering the Molecular Mechanism Underpinning Phage Arbitrium Communication Systems.

Mol Cell 2019 Feb 6. Epub 2019 Feb 6.

Instituto de Biomedicina de Valencia (IBV-CSIC) and CIBER de Enfermedades Raras (CIBERER), 46010 Valencia, Spain. Electronic address:

Bacillus phages use a communication system, termed "arbitrium," to coordinate lysis-lysogeny decisions. Arbitrium communication is mediated by the production and secretion of a hexapeptide (AimP) during lytic cycle. Once internalized, AimP reduces the expression of the negative regulator of lysogeny, AimX, by binding to the transcription factor, AimR, promoting lysogeny. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.025DOI Listing
February 2019

Oncogenic Notch Promotes Long-Range Regulatory Interactions within Hyperconnected 3D Cliques.

Mol Cell 2019 Feb 5. Epub 2019 Feb 5.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Chromatin loops enable transcription-factor-bound distal enhancers to interact with their target promoters to regulate transcriptional programs. Although developmental transcription factors such as active forms of Notch can directly stimulate transcription by activating enhancers, the effect of their oncogenic subversion on the 3D organization of cancer genomes is largely undetermined. By mapping chromatin looping genome-wide in Notch-dependent triple-negative breast cancer and B cell lymphoma, we show that beyond the well-characterized role of Notch as an activator of distal enhancers, Notch regulates its direct target genes by instructing enhancer repositioning. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10972765193000
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http://dx.doi.org/10.1016/j.molcel.2019.01.006DOI Listing
February 2019
2 Reads

Dual Role of Mitochondrial Porin in Metabolite Transport across the Outer Membrane and Protein Transfer to the Inner Membrane.

Mol Cell 2019 Jan 10. Epub 2019 Jan 10.

Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany. Electronic address:

The mitochondrial inner membrane harbors a large number of metabolite carriers. The precursors of carrier proteins are synthesized in the cytosol and imported into mitochondria by the translocase of the outer membrane (TOM) and the carrier translocase of the inner membrane (TIM22). Molecular chaperones in the cytosol and intermembrane space bind to the hydrophobic precursors to prevent their aggregation. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.014DOI Listing
January 2019

Porin Associates with Tom22 to Regulate the Mitochondrial Protein Gate Assembly.

Mol Cell 2019 Jan 31. Epub 2019 Jan 31.

Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku, Kyoto 603-8555, Japan; Institute for Protein Dynamics, Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku, Kyoto 603-8555, Japan. Electronic address:

Mitochondria import nearly all of their resident proteins from the cytosol, and the TOM complex functions as their entry gate. The TOM complex undergoes a dynamic conversion between the majority population of a three-channel gateway ("trimer") and the minor population that lacks Tom22 and has only two Tom40 channels ("dimer"). Here, we found that the porin Por1 acts as a sink to bind newly imported Tom22. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.003DOI Listing
January 2019
14.018 Impact Factor

Dynamic Processing of Displacement Loops during Recombinational DNA Repair.

Mol Cell 2019 Jan 25. Epub 2019 Jan 25.

Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA 95616, USA; Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA 95616, USA. Electronic address:

Displacement loops (D-loops) are pivotal intermediates of homologous recombination (HR), a universal DNA double strand break (DSB) repair pathway. We developed a versatile assay for the physical detection of D-loops in vivo, which enabled studying the kinetics of their formation and defining the activities controlling their metabolism. Nascent D-loops are detected within 2 h of DSB formation and extended in a delayed fashion in a genetic system designed to preclude downstream repair steps. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.005DOI Listing
January 2019

Activation of the Endonuclease that Defines mRNA 3' Ends Requires Incorporation into an 8-Subunit Core Cleavage and Polyadenylation Factor Complex.

Mol Cell 2019 Jan 31. Epub 2019 Jan 31.

MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. Electronic address:

Cleavage and polyadenylation factor (CPF/CPSF) is a multi-protein complex essential for formation of eukaryotic mRNA 3' ends. CPF cleaves pre-mRNAs at a specific site and adds a poly(A) tail. The cleavage reaction defines the 3' end of the mature mRNA, and thus the activity of the endonuclease is highly regulated. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.023DOI Listing
January 2019
2 Reads

Reprogramming of Meiotic Chromatin Architecture during Spermatogenesis.

Mol Cell 2019 Feb;73(3):547-561.e6

Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, School of Life Sciences, THU-PKU Center for Life Science, Tsinghua University, Beijing 100084, China. Electronic address:

Chromatin organization undergoes drastic reconfiguration during gametogenesis. However, the molecular reprogramming of three-dimensional chromatin structure in this process remains poorly understood for mammals, including primates. Here, we examined three-dimensional chromatin architecture during spermatogenesis in rhesus monkey using low-input Hi-C. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.11.019DOI Listing
February 2019

R-Loops as Cellular Regulators and Genomic Threats.

Mol Cell 2019 Feb;73(3):398-411

Department of Chemical and Systems Biology, Stanford University School of Medicine, 318 Campus Drive, Stanford, CA 94305-5441, USA. Electronic address:

During transcription, the nascent RNA strand can base pair with its template DNA, displacing the non-template strand as ssDNA and forming a structure called an R-loop. R-loops are common across many domains of life and cause DNA damage in certain contexts. In this review, we summarize recent results implicating R-loops as important regulators of cellular processes such as transcription termination, gene regulation, and DNA repair. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.024DOI Listing
February 2019

A Fruitful Discovery: Can Gut Bacteria Control Hyperactive Behavior?

Mol Cell 2019 Feb;73(3):395-397

Biodesign Swette Center for Environmental Biotechnology, Arizona State University, Tempe, AZ, USA; Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, USA; School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ, USA. Electronic address:

In a recent publication in Nature, Schretter et al. (2018) demonstrated in the fruit fly Drosophila melanogaster how an enzyme from specific gut bacteria (Lactobacillus brevis) regulates locomotor behavior through carbohydrate metabolism. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.031DOI Listing
February 2019

Pach-ing It in: The Peculiar Organization of Mammalian Pachytene Chromosomes.

Mol Cell 2019 Feb;73(3):392-394

Department of Biology, Emory University, 1510 Clifton Road NE, Atlanta, GA 30322, USA. Electronic address:

In this issue of Molecular Cell, Wang et al. (2019) use Hi-C to visualize at high resolution the complex reprogramming of chromatin architecture during spermatogenesis in rhesus monkeys and mice. They find that pachytene spermatocytes have a unique chromosome organization that may result from the presence of the synaptonemal complex and transcription-associated proteins. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.030DOI Listing
February 2019

Inflammasome Inhibition Links IRGM to Innate Immunity.

Mol Cell 2019 Feb;73(3):391-392

B Cell Molecular Immunology Section, Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

IRGM is a risk factor for several inflammatory diseases, yet no direct link to immune regulation had been shown. In this issue of Molecular Cell, Mehto et al. (2019) report that IRGM limits NLRP3 inflammasome activation-by both direct inhibition of NLRP3/ASC oligomerization and selective autophagic destruction of NLRP3/ASC. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.029DOI Listing
February 2019

Rad5 Recruits Error-Prone DNA Polymerases for Mutagenic Repair of ssDNA Gaps on Undamaged Templates.

Mol Cell 2019 Jan 31. Epub 2019 Jan 31.

Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, ON M5S 3E1, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada. Electronic address:

Post-replication repair (PRR) allows tolerance of chemical- and UV-induced DNA base lesions in both an error-free and an error-prone manner. In classical PRR, PCNA monoubiquitination recruits translesion synthesis (TLS) DNA polymerases that can replicate through lesions. We find that PRR responds to DNA replication stress that does not cause base lesions. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.001DOI Listing
January 2019

Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1.

Mol Cell 2019 Jan 23. Epub 2019 Jan 23.

Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA. Electronic address:

Mutations in PTEN-induced kinase 1 (PINK1) can cause recessive early-onset Parkinson's disease (PD). Import arrest results in PINK1 kinase activation specifically on damaged mitochondria, triggering Parkin-mediated mitophagy. Here, we show that PINK1 import is less dependent on Tim23 than on mitochondrial membrane potential (ΔΨm). Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.002DOI Listing
January 2019

Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance.

Mol Cell 2019 Jan 24. Epub 2019 Jan 24.

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. Electronic address:

The MHC class I antigen presentation system enables T cell immunosurveillance of cancers and viruses. A substantial fraction of the immunopeptidome derives from rapidly degraded nascent polypeptides (DRiPs). By knocking down each of the 80 ribosomal proteins, we identified proteins that modulate peptide generation without altering source protein expression. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.020DOI Listing
January 2019

ELTA: Enzymatic Labeling of Terminal ADP-Ribose.

Mol Cell 2019 Jan 25. Epub 2019 Jan 25.

Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Molecular Biology and Genetics, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address:

ADP-ribosylation refers to the addition of one or more ADP-ribose groups onto proteins. The attached ADP-ribose monomers or polymers, commonly known as poly(ADP-ribose) (PAR), modulate the activities of the modified substrates or their binding affinities to other proteins. However, progress in this area is hindered by a lack of tools to investigate this protein modification. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.022DOI Listing
January 2019

Mechano-regulation of Peptide-MHC Class I Conformations Determines TCR Antigen Recognition.

Mol Cell 2019 Jan 19. Epub 2019 Jan 19.

National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

TCRs recognize cognate pMHCs to initiate T cell signaling and adaptive immunity. Mechanical force strengthens TCR-pMHC interactions to elicit agonist-specific catch bonds to trigger TCR signaling, but the underlying dynamic structural mechanism is unclear. We combined steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, and functional assays to collectively demonstrate that mechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force, resulting in TCR-pMHC catch bonds and T cell activation. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10972765183107
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http://dx.doi.org/10.1016/j.molcel.2018.12.018DOI Listing
January 2019
4 Reads

A Code of Mono-phosphorylation Modulates the Function of RB.

Mol Cell 2019 Jan 30. Epub 2019 Jan 30.

Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149 13th Street, Charlestown, MA 02129, USA. Electronic address:

Hyper-phosphorylation of RB controls its interaction with E2F and inhibits its tumor suppressor properties. However, during G1 active RB can be mono-phosphorylated on any one of 14 CDK phosphorylation sites. Here, we used quantitative proteomics to profile protein complexes formed by each mono-phosphorylated RB isoform (mP-RB) and identified the associated transcriptional outputs. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.01.004DOI Listing
January 2019

A Functional Mini-Integrase in a Two-Protein-type V-C CRISPR System.

Mol Cell 2019 Jan 8. Epub 2019 Jan 8.

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA; MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Gladstone Institutes, San Francisco, CA 94158, USA. Electronic address:

CRISPR-Cas immunity requires integration of short, foreign DNA fragments into the host genome at the CRISPR locus, a site consisting of alternating repeat sequences and foreign-derived spacers. In most CRISPR systems, the proteins Cas1 and Cas2 form the integration complex and are both essential for DNA acquisition. Most type V-C and V-D systems lack the cas2 gene and have unusually short CRISPR repeats and spacers. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10972765183106
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http://dx.doi.org/10.1016/j.molcel.2018.12.015DOI Listing
January 2019
4 Reads

R-Loops Enhance Polycomb Repression at a Subset of Developmental Regulator Genes.

Mol Cell 2019 Jan 14. Epub 2019 Jan 14.

Berlin Institute for Medical Systems Biology, Max Delbrueck Centre for Molecular Medicine, Berlin-Buch 13092, Germany; Berlin Institute of Health, Berlin, Germany; Institute for Biology, Humboldt-Universitat zu Berlin, Berlin, Germany. Electronic address:

R-loops are three-stranded nucleic acid structures that form during transcription, especially over unmethylated CpG-rich promoters of active genes. In mouse embryonic stem cells (mESCs), CpG-rich developmental regulator genes are repressed by the Polycomb complexes PRC1 and PRC2. Here, we show that R-loops form at a subset of Polycomb target genes, and we investigate their contribution to Polycomb repression. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.016DOI Listing
January 2019

BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.

Mol Cell 2019 Jan 10. Epub 2019 Jan 10.

Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA. Electronic address:

BRCA1 functions at two distinct steps during homologous recombination (HR). Initially, it promotes DNA end resection, and subsequently it recruits the PALB2 and BRCA2 mediator complex, which stabilizes RAD51-DNA nucleoprotein filaments. Loss of 53BP1 rescues the HR defect in BRCA1-deficient cells by increasing resection, suggesting that BRCA1's downstream role in RAD51 loading is dispensable when 53BP1 is absent. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10972765183106
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http://dx.doi.org/10.1016/j.molcel.2018.12.010DOI Listing
January 2019
10 Reads

Pacer Is a Mediator of mTORC1 and GSK3-TIP60 Signaling in Regulation of Autophagosome Maturation and Lipid Metabolism.

Mol Cell 2019 Jan 19. Epub 2019 Jan 19.

Department of Biochemistry, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address:

mTORC1 and GSK3 play critical roles in early stages of (macro)autophagy, but how they regulate late steps of autophagy remains poorly understood. Here we show that mTORC1 and GSK3-TIP60 signaling converge to modulate autophagosome maturation through Pacer, an autophagy regulator that was identified in our recent study. Hepatocyte-specific Pacer knockout in mice results in impaired autophagy flux, glycogen and lipid accumulation, and liver fibrosis. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.017DOI Listing
January 2019
1 Read

High-Resolution Ribosome Profiling Defines Discrete Ribosome Elongation States and Translational Regulation during Cellular Stress.

Mol Cell 2019 Jan 11. Epub 2019 Jan 11.

Howard Hughes Medical Institute (HHMI); Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

Ribosomes undergo substantial conformational changes during translation elongation to accommodate incoming aminoacyl-tRNAs and translocate along the mRNA template. We used multiple elongation inhibitors and chemical probing to define ribosome conformational states corresponding to differently sized ribosome-protected mRNA fragments (RPFs) generated by ribosome profiling. We show, using various genetic and environmental perturbations, that short 20-22 or classical 27-29 nucleotide RPFs correspond to ribosomes with open or occupied ribosomal A sites, respectively. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.009DOI Listing
January 2019

Genetic Screens Reveal FEN1 and APEX2 as BRCA2 Synthetic Lethal Targets.

Mol Cell 2019 Jan 24. Epub 2019 Jan 24.

Howard Hughes Medical Institute, Department of Genetics, Ludwig Center, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address:

BRCA1 or BRCA2 inactivation drives breast and ovarian cancer but also creates vulnerability to poly(ADP-ribose) polymerase (PARP) inhibitors. To search for additional targets whose inhibition is synthetically lethal in BRCA2-deficient backgrounds, we screened two pairs of BRCA2 isogenic cell lines with DNA-repair-focused small hairpin RNA (shRNA) and CRISPR (clustered regularly interspaced short palindromic repeats)-based libraries. We found that BRCA2-deficient cells are selectively dependent on multiple pathways including base excision repair, ATR signaling, and splicing. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.008DOI Listing
January 2019

RIM and RIM-BP Form Presynaptic Active-Zone-like Condensates via Phase Separation.

Mol Cell 2019 Jan 15. Epub 2019 Jan 15.

Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Center of Systems Biology and Human Health, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. Electronic address:

Both the timing and kinetics of neurotransmitter release depend on the positioning of clustered Ca channels in active zones to docked synaptic vesicles on presynaptic plasma membranes. However, how active zones form is not known. Here, we show that RIM and RIM-BP, via specific multivalent bindings, form dynamic and condensed assemblies through liquid-liquid phase separation. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.007DOI Listing
January 2019
1 Read

Light Regulates Plant Alternative Splicing through the Control of Transcriptional Elongation.

Mol Cell 2019 Jan 15. Epub 2019 Jan 15.

Universidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, Departamento de Fisiología, Biología Molecular y Celular and CONICET-UBA, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), (C1428EHA), Buenos Aires, Argentina. Electronic address:

Light makes carbon fixation possible, allowing plant and animal life on Earth. We have previously shown that light regulates alternative splicing in plants. Light initiates a chloroplast retrograde signaling that regulates nuclear alternative splicing of a subset of Arabidopsis thaliana transcripts. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.005DOI Listing
January 2019
1 Read

Architecture of Microcin B17 Synthetase: An Octameric Protein Complex Converting a Ribosomally Synthesized Peptide into a DNA Gyrase Poison.

Mol Cell 2019 Jan 16. Epub 2019 Jan 16.

Centre for Life Sciences, Skolkovo Institute of Science and Technology, 143026 Moscow, Russia; Institute of Gene Biology of the Russian Academy of Sciences, 119334 Moscow, Russia; Waksman Institute for Microbiology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. Electronic address:

The introduction of azole heterocycles into a peptide backbone is the principal step in the biosynthesis of numerous compounds with therapeutic potential. One of them is microcin B17, a bacterial topoisomerase inhibitor whose activity depends on the conversion of selected serine and cysteine residues of the precursor peptide to oxazoles and thiazoles by the McbBCD synthetase complex. Crystal structures of McbBCD reveal an octameric BCD complex with two bound substrate peptides. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.11.032DOI Listing
January 2019
1 Read

An Isoprene Lipid-Binding Protein Promotes Eukaryotic Coenzyme Q Biosynthesis.

Mol Cell 2019 Jan 15. Epub 2019 Jan 15.

Morgridge Institute for Research, Madison, WI 53715, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53715, USA. Electronic address:

The biosynthesis of coenzyme Q presents a paradigm for how cells surmount hydrophobic barriers in lipid biology. In eukaryotes, CoQ precursors-among nature's most hydrophobic molecules-must somehow be presented to a series of enzymes peripherally associated with the mitochondrial inner membrane. Here, we reveal that this process relies on custom lipid-binding properties of COQ9. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10972765183100
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http://dx.doi.org/10.1016/j.molcel.2018.11.033DOI Listing
January 2019
5 Reads

Single-Molecule Imaging of mRNA Localization and Regulation during the Integrated Stress Response.

Mol Cell 2019 Jan 4. Epub 2019 Jan 4.

Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland. Electronic address:

Biological phase transitions form membrane-less organelles that generate distinct cellular environments. How molecules are partitioned between these compartments and the surrounding cellular space and the functional consequence of this localization is not well understood. Here, we report the localization of mRNA to stress granules (SGs) and processing bodies (PBs) and its effect on translation and degradation during the integrated stress response. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.006DOI Listing
January 2019
2 Reads

Think We Understand the Role of DRP1 in Mitochondrial Biology? Zinc Again!

Mol Cell 2019 Jan;73(2):197-198

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:

In this issue of Molecular Cell, Cho et al. (2019) identify a mechanism by which the mitochondrial division machinery provides selective pressure to identify dysfunctional organelles through the coordinated action of DRP1, Zip1, and Zn transport into mitochondria. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.024DOI Listing
January 2019
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F-Box Protein-Mediated Resistance to PARP Inhibitor Therapy.

Mol Cell 2019 Jan;73(2):195-196

Department of Biomedical Informatics, The Ohio State University and The OSU Comprehensive Cancer Center, Columbus, OH, USA. Electronic address:

PARP inhibitor (PARPi) therapy targets BRCA1/2 mutant tumor cells, but acquired resistance limits its effectiveness. In this issue of Molecular Cell, Marzio et al. (2019) identify a novel mechanism of resistance to PARPi through regulation of RAD51 protein stability via an SCF ubiquitin ligase dependent on EMI1. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.019DOI Listing
January 2019
4 Reads

The RNA-Binding Protein PUM2 Impairs Mitochondrial Dynamics and Mitophagy During Aging.

Mol Cell 2019 Jan 11. Epub 2019 Jan 11.

Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. Electronic address:

Little information is available about how post-transcriptional mechanisms regulate the aging process. Here, we show that the RNA-binding protein Pumilio2 (PUM2), which is a translation repressor, is induced upon aging and acts as a negative regulator of lifespan and mitochondrial homeostasis. Multi-omics and cross-species analyses of PUM2 function show that it inhibits the translation of the mRNA encoding for the mitochondrial fission factor (Mff), thereby impairing mitochondrial fission and mitophagy. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.11.034DOI Listing
January 2019
15 Reads

RNA Polymerase II CTD Tyrosine 1 Is Required for Efficient Termination by the Nrd1-Nab3-Sen1 Pathway.

Mol Cell 2018 Dec 28. Epub 2018 Dec 28.

Institut de recherches cliniques de Montréal, 110 Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada; Département de Médecine, Faculté de Médecine, Université de Montréal, 2900 Boulevard Edouard-Montpetit, Montréal, QC H3T 1J4, Canada. Electronic address:

In Saccharomyces cerevisiae, transcription termination at protein-coding genes is coupled to the cleavage of the nascent transcript, whereas most non-coding RNA transcription relies on a cleavage-independent termination pathway involving Nrd1, Nab3, and Sen1 (NNS). Termination involves RNA polymerase II CTD phosphorylation, but a systematic analysis of the contribution of individual residues would improve our understanding of the role of the CTD in this process. Here we investigated the effect of mutating phosphorylation sites in the CTD on termination. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.002DOI Listing
December 2018
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BUD13 Promotes a Type I Interferon Response by Countering Intron Retention in Irf7.

Mol Cell 2018 Dec 28. Epub 2018 Dec 28.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address:

Intron retention (IR) has emerged as an important mechanism of gene expression control, but the factors controlling IR events remain poorly understood. We observed consistent IR in one intron of the Irf7 gene and identified BUD13 as an RNA-binding protein that acts at this intron to increase the amount of successful splicing. Deficiency in BUD13 was associated with increased IR, decreased mature Irf7 transcript and protein levels, and consequently a dampened type I interferon response, which compromised the ability of BUD13-deficient macrophages to withstand vesicular stomatitis virus (VSV) infection. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.11.038DOI Listing
December 2018
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The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2.

Mol Cell 2019 Jan 4. Epub 2019 Jan 4.

Program in Epithelial Biology, Stanford University, Stanford, CA 94305, USA; Program in Cancer Biology, Stanford University, Stanford, CA 94305, USA; VA Palo Alto Healthcare System, Palo Alto, CA 94304, USA. Electronic address:

Proximity-dependent biotin labeling (BioID) may identify new targets for cancers driven by difficult-to-drug oncogenes such as Ras. Therefore, BioID was used with wild-type (WT) and oncogenic mutant (MT) H-, K-, and N-Ras, identifying known interactors, including Raf and PI3K, as well as a common set of 130 novel proteins proximal to all Ras isoforms. A CRISPR screen of these proteins for Ras dependence identified mTOR, which was also found proximal to MT Ras in human tumors. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.001DOI Listing
January 2019
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Efficient Pre-mRNA Cleavage Prevents Replication-Stress-Associated Genome Instability.

Mol Cell 2018 Dec 24. Epub 2018 Dec 24.

Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland. Electronic address:

Cellular mechanisms that safeguard genome integrity are often subverted in cancer. To identify cancer-related genome caretakers, we employed a convergent multi-screening strategy coupled to quantitative image-based cytometry and ranked candidate genes according to multivariate readouts reflecting viability, proliferative capacity, replisome integrity, and DNA damage signaling. This unveiled regulators of replication stress resilience, including components of the pre-mRNA cleavage and polyadenylation complex. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.11.036DOI Listing
December 2018
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Mechanistic Insights into the cis- and trans-Acting DNase Activities of Cas12a.

Mol Cell 2019 Feb 10;73(3):589-600.e4. Epub 2019 Jan 10.

Department of Biochemistry, University of Zurich, 8057 Zurich, Switzerland. Electronic address:

CRISPR-Cas12a (Cpf1) is an RNA-guided DNA-cutting nuclease that has been repurposed for genome editing. Upon target DNA binding, Cas12a cleaves both the target DNA in cis and non-target single-stranded DNAs (ssDNAs) in trans. To elucidate the molecular basis for both DNase cleavage modes, we performed structural and biochemical studies on Francisella novicida Cas12a. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.11.021DOI Listing
February 2019
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Multisite Phosphorylation of S6K1 Directs a Kinase Phospho-code that Determines Substrate Selection.

Mol Cell 2019 Feb 3;73(3):446-457.e6. Epub 2019 Jan 3.

Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address:

Multisite phosphorylation of kinases can induce on-off or graded regulation of catalytic activity; however, its influence on substrate specificity remains unclear. Here, we show that multisite phosphorylation of ribosomal protein S6 kinase 1 (S6K1) alters target selection. Agonist-inducible phosphorylation of glutamyl-prolyl tRNA synthetase (EPRS) by S6K1 in monocytes and adipocytes requires not only canonical phosphorylation at Thr by mTORC1 but also phosphorylation at Ser and Ser in the C terminus by cyclin-dependent kinase 5 (Cdk5). Read More

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http://dx.doi.org/10.1016/j.molcel.2018.11.017DOI Listing
February 2019
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The Crohn's Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy.

Mol Cell 2019 Feb 3;73(3):429-445.e7. Epub 2019 Jan 3.

Cell Biology and Infectious Diseases Unit, Institute of Life Sciences, Bhubaneswar 751023, India. Electronic address:

Several large-scale genome-wide association studies genetically linked IRGM to Crohn's disease and other inflammatory disorders in which the IRGM appears to have a protective function. However, the mechanism by which IRGM accomplishes this anti-inflammatory role remains unclear. Here, we reveal that IRGM/Irgm1 is a negative regulator of the NLRP3 inflammasome activation. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372082PMC
February 2019
13 Reads
14.018 Impact Factor

RNA Polymerase I Activators Count and Adjust Ribosomal RNA Gene Copy Number.

Mol Cell 2018 Dec 20. Epub 2018 Dec 20.

Laboratory of Genome Regeneration, Research Center for Biological Visualization, The Institute for Quantitative Biosciences (IQB), 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; Collaborative Research Institute for Innovative Microbiology, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address:

Ribosome is the most abundant RNA-protein complex in a cell, and many copies of the ribosomal RNA gene (rDNA) have to be maintained. However, arrays of tandemly repeated rDNA genes can lose the copies by intra-repeat recombination. Loss of the rDNA copies of Saccharomyces cerevisiae is counteracted by gene amplification whereby the number of rDNA repeats stabilizes around 150 copies, suggesting the presence of a monitoring mechanism that counts and adjusts the number. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.11.029DOI Listing
December 2018
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The Cell-Death-Associated Polymer PAR Feeds Forward α-Synuclein Toxicity in Parkinson's Disease.

Mol Cell 2019 Jan;73(1):5-6

Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. Electronic address:

Parkinson's disease (PD) is characterized by protein aggregates of α-synuclein in neurons. In a recent issue of Science, Kam et al. (2018) revealed a feedforward loop in which α-synuclein increases the levels of poly(adenosine 5'-diphosphate-ribose) (PAR) that in turn causes α-synuclein aggregates to be more toxic. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.011DOI Listing
January 2019
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An Arginine Nexus in the RNA Polymerase II CTD.

Authors:
Jeffry L Corden

Mol Cell 2019 Jan;73(1):3-4

Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

In this issue of Molecular Cell,Sharma et al. (2019) show that normal cell growth requires conversion of an arginine residue in the RNA polymerase II C-terminal domain (CTD) to citrulline, uncovering a potential regulatory pathway involving opposing arginine modifications. Read More

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http://dx.doi.org/10.1016/j.molcel.2018.12.013DOI Listing
January 2019
1 Read