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Nature Structural & Molecular Biology

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https://www.readbyqxmd.com/read/28628087/chromatin-enriched-lncrnas-can-act-as-cell-type-specific-activators-of-proximal-gene-transcription
#1
Michael S Werner, Matthew A Sullivan, Rohan N Shah, Rangarajan D Nadadur, Adrian T Grzybowski, Vasiliy Galat, Ivan P Moskowitz, Alexander J Ruthenburg
We recently described a new class of long noncoding RNAs (lncRNAs) that are distinguished by especially tight chromatin association and whose presence is strongly correlated to expression of nearby genes. Here, we examine the cis-enhancer mechanism of this class of chromatin-enriched RNA (cheRNA) across multiple human cell lines. cheRNAs are largely cell type specific and provide the most reliable chromatin signature to predict cis-gene transcription in every human cell type examined. Targeted depletion of three cheRNAs decreases expression of their neighboring genes, indicating potential co-activator function, and single-molecule fluorescence in situ hybridization (smFISH) of one cheRNA-distal target gene pair suggests a spatial overlap consistent with a role in chromosome looping...
June 19, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28604726/rif1-maintains-telomeres-and-mediates-dna-repair-by-encasing-dna-ends
#2
Stefano Mattarocci, Julia K Reinert, Richard D Bunker, Gabriele A Fontana, Tianlai Shi, Dominique Klein, Simone Cavadini, Mahamadou Faty, Maksym Shyian, Lukas Hafner, David Shore, Nicolas H Thomä, Ulrich Rass
In yeast, Rif1 is part of the telosome, where it inhibits telomerase and checkpoint signaling at chromosome ends. In mammalian cells, Rif1 is not telomeric, but it suppresses DNA end resection at chromosomal breaks, promoting repair by nonhomologous end joining (NHEJ). Here, we describe crystal structures for the uncharacterized and conserved ∼125-kDa N-terminal domain of Rif1 from Saccharomyces cerevisiae (Rif1-NTD), revealing an α-helical fold shaped like a shepherd's crook. We identify a high-affinity DNA-binding site in the Rif1-NTD that fully encases DNA as a head-to-tail dimer...
June 12, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28581512/structural-basis-for-the-cooperative-allosteric-activation-of-the-free-fatty-acid-receptor-gpr40
#3
Jun Lu, Noel Byrne, John Wang, Gerard Bricogne, Frank K Brown, Harry R Chobanian, Steven L Colletti, Jerry Di Salvo, Brande Thomas-Fowlkes, Yan Guo, Dawn L Hall, Jennifer Hadix, Nicholas B Hastings, Jeffrey D Hermes, Thu Ho, Andrew D Howard, Hubert Josien, Maria Kornienko, Kevin J Lumb, Michael W Miller, Sangita B Patel, Barbara Pio, Christopher W Plummer, Bradley S Sherborne, Payal Sheth, Sarah Souza, Srivanya Tummala, Clemens Vonrhein, Maria Webb, Samantha J Allen, Jennifer M Johnston, Adam B Weinglass, Sujata Sharma, Stephen M Soisson
Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle...
June 5, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28581511/rna-fate-determination-through-cotranscriptional-adenosine-methylation-and-microprocessor-binding
#4
Philip Knuckles, Sarah H Carl, Michael Musheev, Christof Niehrs, Alice Wenger, Marc Bühler
Eukaryotic gene expression is heavily regulated at the transcriptional and post-transcriptional levels. An additional layer of regulation occurs co-transcriptionally through processing and decay of nascent transcripts physically associated with chromatin. This process involves RNA interference (RNAi) machinery and is well documented in yeast, but little is known about its conservation in mammals. Here we show that Dgcr8 and Drosha physically associate with chromatin in murine embryonic stem cells (mES), specifically with a subset of transcribed coding and noncoding genes...
June 5, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28553961/structural-analysis-of-mdm2-ring-separates-degradation-from-regulation-of-p53-transcription-activity
#5
Koji Nomura, Marta Klejnot, Dominika Kowalczyk, Andreas K Hock, Gary J Sibbet, Karen H Vousden, Danny T Huang
MDM2-MDMX complexes bind the p53 tumor-suppressor protein, inhibiting p53's transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response, but their use in the treatment of cancers that retain wild-type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2-MDMX-E2(UbcH5B)-ubiquitin complex, we designed MDM2 mutants that prevent E2-ubiquitin binding without altering the RING-domain structure...
May 29, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28530707/a-mili-independent-pirna-biogenesis-pathway-empowers-partial-germline-reprogramming
#6
Lina Vasiliauskaitė, Dimitrios Vitsios, Rebecca V Berrens, Claudia Carrieri, Wolf Reik, Anton J Enright, Dónal O'Carroll
In mice, the pathway involving PIWI and PIWI-interacting RNA (PIWI-piRNA) is essential to re-establish transposon silencing during male-germline reprogramming. The cytoplasmic PIWI protein MILI mediates piRNA-guided transposon RNA cleavage as well as piRNA amplification. MIWI2's binding to piRNA and its nuclear localization are proposed to be dependent upon MILI function. Here, we demonstrate the existence of a piRNA biogenesis pathway that sustains partial MIWI2 function and reprogramming activity in the absence of MILI...
May 22, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28586330/gathering-by-the-red-sea-highlights-links-between-environment-and-epigenetics
#7
Mo Li, Emiliana Borrelli, Pierre J Magistretti, Juan Carlos Izpisua Belmonte, Paolo Sassone-Corsi, Valerio Orlando
No abstract text is available yet for this article.
June 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28586329/rna-base-pairing-drives-phase-transitions
#8
Anke Sparmann
No abstract text is available yet for this article.
June 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28586328/promoter-interactions-direct-chromatin-folding-in-embryonic-stem-cells
#9
Swastika Sanyal, Lucia Molnarova, Juraj Gregan
No abstract text is available yet for this article.
June 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28586327/a-glimpse-into-chromatin-remodeling
#10
Dale B Wigley, Gregory D Bowman
No abstract text is available yet for this article.
June 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28586326/erratum-molecular-basis-of-telomere-dysfunction-in-human-genetic-diseases
#11
Grzegorz Sarek, Paulina Marzec, Pol Margalef, Simon J Boulton
No abstract text is available yet for this article.
June 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28586325/distinct-mechanisms-obviate-the-potentially-toxic-effects-of-inverted-repeat-alu-elements-on-cellular-rna-metabolism
#12
Reyad A Elbarbary, Lynne E Maquat
No abstract text is available yet for this article.
June 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28586324/frozen-in-action-cryo-em-structure-of-a-gpcr-g-protein-complex
#13
Mithu Baidya, Hemlata Dwivedi, Arun K Shukla
No abstract text is available yet for this article.
June 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28586323/corrigendum-quaternary-contact-in-the-initial-interaction-of-cd4-with-the-hiv-1-envelope-trimer
#14
Qingbo Liu, Priyamvada Acharya, Michael A Dolan, Peng Zhang, Christina Guzzo, Jacky Lu, Alice Kwon, Deepali Gururani, Huiyi Miao, Tatsiana Bylund, Gwo-Yu Chuang, Aliaksandr Druz, Tongqing Zhou, William J Rice, Christoph Wigge, Bridget Carragher, Clinton S Potter, Peter D Kwong, Paolo Lusso
No abstract text is available yet for this article.
June 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28586322/dna-n-6-methyladenine-in-metazoans-functional-epigenetic-mark-or-bystander
#15
Guan-Zheng Luo, Chuan He
The DNA-adenine modification N(6)-methyladenine (6mA), initially thought to be mainly restricted to prokaryotes and certain unicellular eukaryotes, has recently been found in metazoans. Proposed functions vary from gene activation to transposon suppression. However, since most metazoan genomes possess 5-methylcytosine (5mC) as a dominant epigenetic mark, it raises the question of why 6mA is required. This Perspective summarizes the latest discoveries and suggests potential functional roles for 6mA in metazoan genomes...
June 6, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28504696/5-formylcytosine-does-not-change-the-global-structure-of-dna
#16
Jack S Hardwick, Denis Ptchelkine, Afaf H El-Sagheer, Ian Tear, Daniel Singleton, Simon E V Phillips, Andrew N Lane, Tom Brown
The mechanism by which the recently identified DNA modification 5-formylcytosine ((f)C) is recognized by epigenetic writer and reader proteins is not known. Recently, an unusual DNA structure, F-DNA, has been proposed as the basis for enzyme recognition of clusters of (f)C. We used NMR and X-ray crystallography to compare several modified DNA duplexes with unmodified analogs and found that in the crystal state the duplexes all belong to the A family, whereas in solution they are all members of the B family...
June 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28481356/the-myosin-mesa-and-the-basis-of-hypercontractility-caused-by-hypertrophic-cardiomyopathy-mutations
#17
Suman Nag, Darshan V Trivedi, Saswata S Sarkar, Arjun S Adhikari, Margaret S Sunitha, Shirley Sutton, Kathleen M Ruppel, James A Spudich
Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in β-cardiac myosin and myosin-binding protein-C (MyBP-C). Changes in the contractile parameters of myosin measured so far do not explain the clinical hypercontractility caused by such mutations. We propose that hypercontractility is due to an increase in the number of myosin heads (S1) that are accessible for force production. In support of this hypothesis, we demonstrate myosin tail (S2)-dependent functional regulation of actin-activated human β-cardiac myosin ATPase...
June 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28459447/human-ctp-synthase-filament-structure-reveals-the-active-enzyme-conformation
#18
Eric M Lynch, Derrick R Hicks, Matthew Shepherd, James A Endrizzi, Allison Maker, Jesse M Hansen, Rachael M Barry, Zemer Gitai, Enoch P Baldwin, Justin M Kollman
The universally conserved enzyme CTP synthase (CTPS) forms filaments in bacteria and eukaryotes. In bacteria, polymerization inhibits CTPS activity and is required for nucleotide homeostasis. Here we show that for human CTPS, polymerization increases catalytic activity. The cryo-EM structures of bacterial and human CTPS filaments differ considerably in overall architecture and in the conformation of the CTPS protomer, explaining the divergent consequences of polymerization on activity. The structure of human CTPS filament, the first structure of the full-length human enzyme, reveals a novel active conformation...
June 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28436945/adar1-controls-apoptosis-of-stressed-cells-by-inhibiting-staufen1-mediated-mrna-decay
#19
Masayuki Sakurai, Yusuke Shiromoto, Hiromitsu Ota, Chunzi Song, Andrew V Kossenkov, Jayamanna Wickramasinghe, Louise C Showe, Emmanuel Skordalakes, Hsin-Yao Tang, David W Speicher, Kazuko Nishikura
Both p150 and p110 isoforms of ADAR1 convert adenosine to inosine in double-stranded RNA (dsRNA). ADAR1p150 suppresses the dsRNA-sensing mechanism that activates MDA5-MAVS-IFN signaling in the cytoplasm. In contrast, the biological function of the ADAR1p110 isoform, which is usually located in the nucleus, is largely unknown. Here, we show that stress-activated phosphorylation of ADAR1p110 by MKK6-p38-MSK MAP kinases promotes its binding to Exportin-5 and its export from the nucleus. After translocating to the cytoplasm, ADAR1p110 suppresses apoptosis in stressed cells by protecting many antiapoptotic gene transcripts that contain 3'-untranslated-region dsRNA structures primarily comprising inverted Alu repeats...
June 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28436944/active-and-poised-promoter-states-drive-folding-of-the-extended-hoxb-locus-in-mouse-embryonic-stem-cells
#20
Mariano Barbieri, Sheila Q Xie, Elena Torlai Triglia, Andrea M Chiariello, Simona Bianco, Inês de Santiago, Miguel R Branco, David Rueda, Mario Nicodemi, Ana Pombo
Gene expression states influence the 3D conformation of the genome through poorly understood mechanisms. Here, we investigate the conformation of the murine HoxB locus, a gene-dense genomic region containing closely spaced genes with distinct activation states in mouse embryonic stem (ES) cells. To predict possible folding scenarios, we performed computer simulations of polymer models informed with different chromatin occupancy features that define promoter activation states or binding sites for the transcription factor CTCF...
June 2017: Nature Structural & Molecular Biology
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