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Molecular Cell

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https://www.readbyqxmd.com/read/29681497/capzyme-seq-comprehensively-defines-promoter-sequence-determinants-for-rna-5-capping-with-nad
#1
Irina O Vvedenskaya, Jeremy G Bird, Yuanchao Zhang, Yu Zhang, Xinfu Jiao, Ivan Barvík, Libor Krásný, Megerditch Kiledjian, Deanne M Taylor, Richard H Ebright, Bryce E Nickels
Nucleoside-containing metabolites such as NAD+ can be incorporated as 5' caps on RNA by serving as non-canonical initiating nucleotides (NCINs) for transcription initiation by RNA polymerase (RNAP). Here, we report CapZyme-seq, a high-throughput-sequencing method that employs NCIN-decapping enzymes NudC and Rai1 to detect and quantify NCIN-capped RNA. By combining CapZyme-seq with multiplexed transcriptomics, we determine efficiencies of NAD+ capping by Escherichia coli RNAP for ∼16,000 promoter sequences...
April 18, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29681499/allosteric-activation-dictates-prc2-activity-independent-of-its-recruitment-to-chromatin
#2
Chul-Hwan Lee, Jia-Ray Yu, Sunil Kumar, Ying Jin, Gary LeRoy, Natarajan Bhanu, Syuzo Kaneko, Benjamin A Garcia, Andrew D Hamilton, Danny Reinberg
PRC2 is a therapeutic target for several types of cancers currently undergoing clinical trials. Its activity is regulated by a positive feedback loop whereby its terminal enzymatic product, H3K27me3, is specifically recognized and bound by an aromatic cage present in its EED subunit. The ensuing allosteric activation of the complex stimulates H3K27me3 deposition on chromatin. Here we report a stepwise feedback mechanism entailing key residues within distinctive interfacing motifs of EZH2 or EED that are found to be mutated in cancers and/or Weaver syndrome...
April 13, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29681498/distinct-stimulatory-mechanisms-regulate-the-catalytic-activity-of-polycomb-repressive-complex-2
#3
Chul-Hwan Lee, Marlene Holder, Daniel Grau, Ricardo Saldaña-Meyer, Jia-Ray Yu, Rais Ahmad Ganai, Jenny Zhang, Miao Wang, Gary LeRoy, Marc-Werner Dobenecker, Danny Reinberg, Karim-Jean Armache
The maintenance of gene expression patterns during metazoan development is achieved, in part, by the actions of polycomb repressive complex 2 (PRC2). PRC2 catalyzes mono-, di-, and trimethylation of histone H3 at lysine 27 (H3K27), with H3K27me2/3 being strongly associated with silenced genes. We demonstrate that EZH1 and EZH2, the two mutually exclusive catalytic subunits of PRC2, are differentially activated by various mechanisms. Whereas both PRC2-EZH1 and PRC2-EZH2 are able to catalyze mono- and dimethylation, only PRC2-EZH2 is strongly activated by allosteric modulators and specific chromatin substrates to catalyze trimethylation of H3K27 in mouse embryonic stem cells (mESCs)...
April 13, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29656925/dynamics-of-parkin-dependent-mitochondrial-ubiquitylation-in-induced-neurons-and-model-systems-revealed-by-digital-snapshot-proteomics
#4
Alban Ordureau, Joao A Paulo, Wei Zhang, Tim Ahfeldt, Jiuchun Zhang, Erin F Cohn, Zhonggang Hou, Jin-Mi Heo, Lee L Rubin, Sachdev S Sidhu, Steven P Gygi, J Wade Harper
Flux through kinase and ubiquitin-driven signaling systems depends on the modification kinetics, stoichiometry, primary site specificity, and target abundance within the pathway, yet we rarely understand these parameters and their spatial organization within cells. Here we develop temporal digital snapshots of ubiquitin signaling on the mitochondrial outer membrane in embryonic stem cell-derived neurons, and we model HeLa cell systems upon activation of the PINK1 kinase and PARKIN ubiquitin ligase by proteomic counting of ubiquitylation and phosphorylation events...
April 11, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29656924/cell-cycle-modulation-of-transcription-termination-factor-sen1
#5
Hannah E Mischo, Yujin Chun, Kevin M Harlen, Brendan M Smalec, Somdutta Dhir, L Stirling Churchman, Stephen Buratowski
Many non-coding transcripts (ncRNA) generated by RNA polymerase II in S. cerevisiae are terminated by the Nrd1-Nab3-Sen1 complex. However, Sen1 helicase levels are surprisingly low compared with Nrd1 and Nab3, raising questions regarding how ncRNA can be terminated in an efficient and timely manner. We show that Sen1 levels increase during the S and G2 phases of the cell cycle, leading to increased termination activity of NNS. Overexpression of Sen1 or failure to modulate its abundance by ubiquitin-proteasome-mediated degradation greatly decreases cell fitness...
April 11, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29628309/jmjd6-licenses-er%C3%AE-dependent-enhancer-and-coding-gene-activation-by-modulating-the-recruitment-of-the-carm1-med12-co-activator-complex
#6
Wei-Wei Gao, Rong-Quan Xiao, Wen-Juan Zhang, Yi-Ren Hu, Bing-Ling Peng, Wen-Juan Li, Yao-Hui He, Hai-Feng Shen, Jian-Cheng Ding, Qi-Xuan Huang, Tian-Yi Ye, Ying Li, Zhi-Ying Liu, Rong Ding, Michael G Rosenfeld, Wen Liu
Whereas the actions of enhancers in gene transcriptional regulation are well established, roles of JmjC-domain-containing proteins in mediating enhancer activation remain poorly understood. Here, we report that recruitment of the JmjC-domain-containing protein 6 (JMJD6) to estrogen receptor alpha (ERα)-bound active enhancers is required for RNA polymerase II recruitment and enhancer RNA production on enhancers, resulting in transcriptional pause release of cognate estrogen target genes. JMJD6 is found to interact with MED12 in the mediator complex to regulate its recruitment...
April 4, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29628310/gcn4-binding-in-coding-regions-can-activate-internal-and-canonical-5-promoters-in-yeast
#7
Yashpal Rawal, Răzvan V Chereji, Vishalini Valabhoju, Hongfang Qiu, Josefina Ocampo, David J Clark, Alan G Hinnebusch
Gcn4 is a yeast transcriptional activator induced by amino acid starvation. ChIP-seq analysis revealed 546 genomic sites occupied by Gcn4 in starved cells, representing ∼30% of Gcn4-binding motifs. Surprisingly, only ∼40% of the bound sites are in promoters, of which only ∼60% activate transcription, indicating extensive negative control over Gcn4 function. Most of the remaining ∼300 Gcn4-bound sites are within coding sequences (CDSs), with ∼75 representing the only bound sites near Gcn4-induced genes...
April 2, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29628307/a-stress-response-that-monitors-and-regulates-mrna-structure-is-central-to-cold-shock-adaptation
#8
Yan Zhang, David H Burkhardt, Silvi Rouskin, Gene-Wei Li, Jonathan S Weissman, Carol A Gross
Temperature influences the structural and functional properties of cellular components, necessitating stress responses to restore homeostasis following temperature shift. Whereas the circuitry controlling the heat shock response is well understood, that controlling the E. coli cold shock adaptation program is not. We found that during the growth arrest phase (acclimation) that follows shift to low temperature, protein synthesis increases, and open reading frame (ORF)-wide mRNA secondary structure decreases...
April 2, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29628311/a-family-of-vertebrate-specific-polycombs-encoded-by-the-lcor-lcorl-genes-balance-prc2-subtype-activities
#9
Eric Conway, Emilia Jerman, Evan Healy, Shinsuke Ito, Daniel Holoch, Giorgio Oliviero, Orla Deevy, Eleanor Glancy, Darren J Fitzpatrick, Marlena Mucha, Ariane Watson, Alan M Rice, Paul Chammas, Christine Huang, Indigo Pratt-Kelly, Yoko Koseki, Manabu Nakayama, Tomoyuki Ishikura, Gundula Streubel, Kieran Wynne, Karsten Hokamp, Aoife McLysaght, Claudio Ciferri, Luciano Di Croce, Gerard Cagney, Raphaël Margueron, Haruhiko Koseki, Adrian P Bracken
The polycomb repressive complex 2 (PRC2) consists of core subunits SUZ12, EED, RBBP4/7, and EZH1/2 and is responsible for mono-, di-, and tri-methylation of lysine 27 on histone H3. Whereas two distinct forms exist, PRC2.1 (containing one polycomb-like protein) and PRC2.2 (containing AEBP2 and JARID2), little is known about their differential functions. Here, we report the discovery of a family of vertebrate-specific PRC2.1 proteins, "PRC2 associated LCOR isoform 1" (PALI1) and PALI2, encoded by the LCOR and LCORL gene loci, respectively...
April 1, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29628308/cracking-the-dna-code-for-v-d-j-recombination
#10
Min-Sung Kim, Watchalee Chuenchor, Xuemin Chen, Yanxiang Cui, Xing Zhang, Z Hong Zhou, Martin Gellert, Wei Yang
To initiate V(D)J recombination for generating the adaptive immune response of vertebrates, RAG1/2 recombinase cleaves DNA at a pair of recombination signal sequences, the 12- and 23-RSS. We have determined crystal and cryo-EM structures of RAG1/2 with DNA in the pre-reaction and hairpin-forming complexes up to 2.75 Å resolution. Both protein and DNA exhibit structural plasticity and undergo dramatic conformational changes. Coding-flank DNAs extensively rotate, shift, and deform for nicking and hairpin formation...
March 29, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29606590/structural-basis-of-transcription-inhibition-by-fidaxomicin-lipiarmycin-a3
#11
Wei Lin, Kalyan Das, David Degen, Abhishek Mazumder, Diego Duchi, Dongye Wang, Yon W Ebright, Richard Y Ebright, Elena Sineva, Matthew Gigliotti, Aashish Srivastava, Sukhendu Mandal, Yi Jiang, Yu Liu, Ruiheng Yin, Zhening Zhang, Edward T Eng, Dennis Thomas, Stefano Donadio, Haibo Zhang, Changsheng Zhang, Achillefs N Kapanidis, Richard H Ebright
Fidaxomicin is an antibacterial drug in clinical use for treatment of Clostridium difficile diarrhea. The active ingredient of fidaxomicin, lipiarmycin A3 (Lpm), functions by inhibiting bacterial RNA polymerase (RNAP). Here we report a cryo-EM structure of Mycobacterium tuberculosis RNAP holoenzyme in complex with Lpm at 3.5-Å resolution. The structure shows that Lpm binds at the base of the RNAP "clamp." The structure exhibits an open conformation of the RNAP clamp, suggesting that Lpm traps an open-clamp state...
March 28, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29606591/visualization-of-transvection-in-living-drosophila-embryos
#12
Bomyi Lim, Tyler Heist, Michael Levine, Takashi Fukaya
How remote enhancers interact with appropriate target genes persists as a central mystery in gene regulation. Here, we exploit the properties of transvection to explore enhancer-promoter communication between homologous chromosomes in living Drosophila embryos. We successfully visualized the activation of an MS2-tagged reporter gene by a defined developmental enhancer located in trans on the other homolog. This trans-homolog activation depends on insulator DNAs, which increase the stability-but not the frequency-of homolog pairing...
March 23, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29576527/discovery-and-characterization-of-zufsp-zup1-a-distinct-deubiquitinase-class-important-for-genome-stability
#13
Dominika Kwasna, Syed Arif Abdul Rehman, Jayaprakash Natarajan, Stephen Matthews, Ross Madden, Virginia De Cesare, Simone Weidlich, Satpal Virdee, Ivan Ahel, Ian Gibbs-Seymour, Yogesh Kulathu
Deubiquitinating enzymes (DUBs) are important regulators of ubiquitin signaling. Here, we report the discovery of deubiquitinating activity in ZUFSP/C6orf113. High-resolution crystal structures of ZUFSP in complex with ubiquitin reveal several distinctive features of ubiquitin recognition and catalysis. Our analyses reveal that ZUFSP is a novel DUB with no homology to any known DUBs, leading us to classify ZUFSP as the seventh DUB family. Intriguingly, the minimal catalytic domain does not cleave polyubiquitin...
March 21, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29602742/cas4-dependent-prespacer-processing-ensures-high-fidelity-programming-of-crispr-arrays
#14
Hayun Lee, Yi Zhou, David W Taylor, Dipali G Sashital
CRISPR-Cas immune systems integrate short segments of foreign DNA as spacers into the host CRISPR locus to provide molecular memory of infection. Cas4 proteins are widespread in CRISPR-Cas systems and are thought to participate in spacer acquisition, although their exact function remains unknown. Here we show that Bacillus halodurans type I-C Cas4 is required for efficient prespacer processing prior to Cas1-Cas2-mediated integration. Cas4 interacts tightly with the Cas1 integrase, forming a heterohexameric complex containing two Cas1 dimers and two Cas4 subunits...
March 17, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29576528/zufsp-deubiquitylates-k63-linked-polyubiquitin-chains-to-promote-genome-stability
#15
Peter Haahr, Nikoline Borgermann, Xiaohu Guo, Dimitris Typas, Divya Achuthankutty, Saskia Hoffmann, Robert Shearer, Titia K Sixma, Niels Mailand
Deubiquitylating enzymes (DUBs) enhance the dynamics of the versatile ubiquitin (Ub) code by reversing and regulating cellular ubiquitylation processes at multiple levels. Here we discovered that the uncharacterized human protein ZUFSP (zinc finger with UFM1-specific peptidase domain protein/C6orf113/ZUP1), which has been annotated as a potentially inactive UFM1 protease, and its fission yeast homolog Mug105 define a previously unrecognized class of evolutionarily conserved cysteine protease DUBs. Human ZUFSP selectively interacts with and cleaves long K63-linked poly-Ub chains by means of tandem Ub-binding domains, whereas it displays poor activity toward mono- or di-Ub substrates...
March 9, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29551514/cas13d-is-a-compact-rna-targeting-type-vi-crispr-effector-positively-modulated-by-a-wyl-domain-containing-accessory-protein
#16
Winston X Yan, Shaorong Chong, Huaibin Zhang, Kira S Makarova, Eugene V Koonin, David R Cheng, David A Scott
Bacterial class 2 CRISPR-Cas systems utilize a single RNA-guided protein effector to mitigate viral infection. We aggregated genomic data from multiple sources and constructed an expanded database of predicted class 2 CRISPR-Cas systems. A search for novel RNA-targeting systems identified subtype VI-D, encoding dual HEPN domain-containing Cas13d effectors and putative WYL-domain-containing accessory proteins (WYL1 and WYL-b1 through WYL-b5). The median size of Cas13d proteins is 190 to 300 aa smaller than that of Cas13a-Cas13c...
March 9, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29576526/systematic-characterization-of-stress-induced-rna-granulation
#17
Sim Namkoong, Allison Ho, Yu Mi Woo, Hojoong Kwak, Jun Hee Lee
Upon stress, cytoplasmic mRNA is sequestered to insoluble ribonucleoprotein (RNP) granules, such as the stress granule (SG). Partially due to the belief that translationally suppressed mRNAs are recruited to SGs in bulk, stress-induced dynamic redistribution of mRNA has not been thoroughly characterized. Here, we report that endoplasmic reticulum (ER) stress targets only a small subset of translationally suppressed mRNAs into the insoluble RNP granule fraction (RG). This subset, characterized by extended length and adenylate-uridylate (AU)-rich motifs, is highly enriched with genes critical for cell survival and proliferation...
March 7, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29551515/coordinated-activity-of-y-family-tls-polymerases-and-exo1-protects-non-s-phase-cells-from-uv-induced-cytotoxic-lesions
#18
Sarah Sertic, Antonio Mollica, Ilaria Campus, Stefania Roma, Emanuela Tumini, Andrés Aguilera, Marco Muzi-Falconi
UV-induced photoproducts are responsible for the pathological effects of sunlight. Mutations in nucleotide excision repair (NER) cause severe pathologies characterized by sunlight sensitivity, coupled to elevated predisposition to cancer and/or neurological dysfunctions. We have previously shown that in UV-irradiated non-cycling cells, only a particular subset of lesions activates the DNA damage response (DDR), and this requires NER and EXO1 activities. To define the molecular mechanism acting at these lesions, we demonstrate that Y family TLS polymerases are recruited at NER- and EXO1-positive lesion sites in non-S phase cells...
March 3, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29526696/lkb1-salt-inducible-kinases-and-mef2c-are-linked-dependencies-in-acute-myeloid-leukemia
#19
Yusuke Tarumoto, Bin Lu, Tim D D Somerville, Yu-Han Huang, Joseph P Milazzo, Xiaoli S Wu, Olaf Klingbeil, Osama El Demerdash, Junwei Shi, Christopher R Vakoc
The lineage-specific transcription factor (TF) MEF2C is often deregulated in leukemia. However, strategies to target this TF have yet to be identified. Here, we used a domain-focused CRISPR screen to reveal an essential role for LKB1 and its Salt-Inducible Kinase effectors (SIK3, in a partially redundant manner with SIK2) to maintain MEF2C function in acute myeloid leukemia (AML). A key phosphorylation substrate of SIK3 in this context is HDAC4, a repressive cofactor of MEF2C. Consequently, targeting of LKB1 or SIK3 diminishes histone acetylation at MEF2C-bound enhancers and deprives leukemia cells of the output of this essential TF...
February 28, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29526697/inter-chromosomal-contact-properties-in-live-cell-imaging-and-in-hi-c
#20
Philipp G Maass, A Rasim Barutcu, Catherine L Weiner, John L Rinn
Imaging (fluorescence in situ hybridization [FISH]) and genome-wide chromosome conformation capture (Hi-C) are two major approaches to the study of higher-order genome organization in the nucleus. Intra-chromosomal and inter-chromosomal interactions (referred to as non-homologous chromosomal contacts [NHCCs]) have been observed by several FISH-based studies, but locus-specific NHCCs have not been detected by Hi-C. Due to crosslinking, neither of these approaches assesses spatiotemporal properties. Toward resolving the discrepancies between imaging and Hi-C, we sought to understand the spatiotemporal properties of NHCCs in living cells by CRISPR/Cas9 live-cell imaging (CLING)...
February 27, 2018: Molecular Cell
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