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Molecular Cell

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https://www.readbyqxmd.com/read/29225036/transcription-and-remodeling-produce-asymmetrically-unwrapped-nucleosomal-intermediates
#1
Srinivas Ramachandran, Kami Ahmad, Steven Henikoff
Nucleosomes are disrupted during transcription and other active processes, but the structural intermediates during nucleosome disruption in vivo are unknown. To identify intermediates, we mapped subnucleosomal protections in Drosophila cells using Micrococcal Nuclease followed by sequencing. At the first nucleosome position downstream of the transcription start site, we identified unwrapped intermediates, including hexasomes that lack either proximal or distal contacts. Inhibiting topoisomerases or depleting histone chaperones increased unwrapping, whereas inhibiting release of paused RNAPII or reducing RNAPII elongation decreased unwrapping...
December 6, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29225038/cell-cycle-control-by-nuclear-sequestration-of-cdc20-and-cdh1-mrna-in-plant-stem-cells
#2
Weibing Yang, Raymond Wightman, Elliot M Meyerowitz
In eukaryotes, most RNA molecules are exported into the cytoplasm after transcription. Long noncoding RNAs (lncRNAs) reside and function primarily inside the nucleus, but nuclear localization of mRNAs has been considered rare in both animals and plants. Here we show that Arabidopsis anaphase-promoting complex/cyclosome (APC/C) coactivator genes CDC20 and CCS52B (CDH1 ortholog) are co-expressed with their target cyclin B genes (CYCBs) during mitosis. CYCB transcripts can be exported and translated; however, CDC20 and CCS52B mRNAs are confined to the nucleus at prophase, and the cognate proteins are not translated until the redistribution of the mRNAs to the cytoplasm after nuclear envelope breakdown (NEBD) at prometaphase...
December 5, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29225037/understanding-and-sensitizing-density-dependent-persistence-to-quinolone-antibiotics
#3
Arnaud Gutierrez, Saloni Jain, Prerna Bhargava, Meagan Hamblin, Michael A Lobritz, James J Collins
Physiologic and environmental factors can modulate antibiotic activity and thus pose a significant challenge to antibiotic treatment. The quinolone class of antibiotics, which targets bacterial topoisomerases, fails to kill bacteria that have grown to high density; however, the mechanistic basis for this persistence is unclear. Here, we show that exhaustion of the metabolic inputs that couple carbon catabolism to oxidative phosphorylation is a primary cause of growth phase-dependent persistence to quinolone antibiotics...
December 5, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29225039/a-massively-parallel-reporter-assay-of-3-utr-sequences-identifies-in%C3%A2-vivo-rules-for-mrna-degradation
#4
Michal Rabani, Lindsey Pieper, Guo-Liang Chew, Alexander F Schier
The stability of mRNAs is regulated by signals within their sequences, but a systematic and predictive understanding of the underlying sequence rules remains elusive. Here we introduce UTR-seq, a combination of massively parallel reporter assays and regression models, to survey the dynamics of tens of thousands of 3' UTR sequences during early zebrafish embryogenesis. UTR-seq revealed two temporal degradation programs: a maternally encoded early-onset program and a late-onset program that accelerated degradation after zygotic genome activation...
November 30, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29225035/cockayne-s-syndrome-a-and-b-proteins-regulate-transcription-arrest-after-genotoxic-stress-by-promoting-atf3-degradation
#5
Alexey Epanchintsev, Federico Costanzo, Marc-Alexander Rauschendorf, Manuela Caputo, Tao Ye, Lise-Marie Donnio, Luca Proietti-de-Santis, Frederic Coin, Vincent Laugel, Jean-Marc Egly
Cockayne syndrome (CS) is caused by mutations in CSA and CSB. The CSA and CSB proteins have been linked to both promoting transcription-coupled repair and restoring transcription following DNA damage. We show that UV stress arrests transcription of approximately 70% of genes in CSA- or CSB-deficient cells due to the constitutive presence of ATF3 at CRE/ATF sites. We found that CSB, CSA/DDB1/CUL4A, and MDM2 were essential for ATF3 ubiquitination and degradation by the proteasome. ATF3 removal was concomitant with the recruitment of RNA polymerase II and the restart of transcription...
November 30, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29225034/cytosolic-iron-sulfur-assembly-is-evolutionarily-tuned-by-a-cancer-amplified-ubiquitin-ligase
#6
Jenny L Weon, Seung Wook Yang, Patrick Ryan Potts
The cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) pathway functions to incorporate inorganic Fe-S cofactors into a variety of proteins, including several DNA repair enzymes. However, the mechanisms regulating the CIA pathway are unknown. We describe here that the MAGE-F1-NSE1 E3 ubiquitin ligase regulates the CIA pathway through ubiquitination and degradation of the CIA-targeting protein MMS19. Overexpression or knockout of MAGE-F1 altered Fe-S incorporation into MMS19-dependent DNA repair enzymes, DNA repair capacity, sensitivity to DNA-damaging agents, and iron homeostasis...
November 30, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29225033/mutant-p53-gains-its-function-via-c-myc-activation-upon-cdk4-phosphorylation-at-serine-249-and-consequent-pin1-binding
#7
Peng Liao, Shelya X Zeng, Xiang Zhou, Tianjian Chen, Fen Zhou, Bo Cao, Ji Hoon Jung, Giannino Del Sal, Shiwen Luo, Hua Lu
TP53 missense mutations significantly influence the development and progression of various human cancers via their gain of new functions (GOF) through different mechanisms. Here we report a unique mechanism underlying the GOF of p53-R249S (p53-RS), a p53 mutant frequently detected in human hepatocellular carcinoma (HCC) that is highly related to hepatitis B infection and aflatoxin B1. A CDK inhibitor blocks p53-RS's nuclear translocation in HCC, whereas CDK4 interacts with p53-RS in the G1/S phase of the cells, phosphorylates it, and enhances its nuclear localization...
November 23, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29198561/transcriptome-wide-analysis-of-roles-for-trna-modifications-in-translational-regulation
#8
Hsin-Jung Chou, Elisa Donnard, H Tobias Gustafsson, Manuel Garber, Oliver J Rando
Covalent nucleotide modifications in noncoding RNAs affect a plethora of biological processes, and new functions continue to be discovered even for well-known modifying enzymes. To systematically compare the functions of a large set of noncoding RNA modifications in gene regulation, we carried out ribosome profiling in budding yeast to characterize 57 nonessential genes involved in tRNA modification. Deletion mutants exhibited a range of translational phenotypes, with enzymes known to modify anticodons, or non-tRNA substrates such as rRNA, exhibiting the most dramatic translational perturbations...
November 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29153394/vcp-p97-mediated-unfolding-as-a-principle-in-protein-homeostasis-and-signaling
#9
REVIEW
Johannes van den Boom, Hemmo Meyer
The AAA+-type ATPase p97 governs an ever-expanding number of cellular processes reaching from degradation of damaged proteins and organelles to key signaling events and chromatin regulation with thousands of client proteins. With its relevance for cellular homeostasis and genome stability, it is linked to muscular and neuronal degeneration and, conversely, constitutes an attractive anti-cancer drug target. Its molecular function is ATP-driven protein unfolding, which is directed by ubiquitin and assisted by a host of cofactor proteins...
November 15, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29153393/protein-based-inheritance-epigenetics-beyond-the-chromosome
#10
REVIEW
Zachary H Harvey, Yiwen Chen, Daniel F Jarosz
Epigenetics refers to changes in phenotype that are not rooted in DNA sequence. This phenomenon has largely been studied in the context of chromatin modification. Yet many epigenetic traits are instead linked to self-perpetuating changes in the individual or collective activity of proteins. Most such proteins are prions (e.g., [PSI+], [URE3], [SWI+], [MOT3+], [MPH1+], [LSB+], and [GAR+]), which have the capacity to adopt at least one conformation that self-templates over long biological timescales. This allows them to serve as protein-based epigenetic elements that are readily broadcast through mitosis and meiosis...
November 15, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29153392/polycomb-repressive-complex-2-methylates-elongin-a-to-regulate-transcription
#11
M Behfar Ardehali, Anthony Anselmo, Jesse C Cochrane, Sharmistha Kundu, Ruslan I Sadreyev, Robert E Kingston
Polycomb repressive complex 2 (PRC2-EZH2) methylates histone H3 at lysine 27 (H3K27) and is required to maintain gene repression during development. Misregulation of PRC2 is linked to a range of neoplastic malignancies, which is believed to involve methylation of H3K27. However, the full spectrum of non-histone substrates of PRC2 that might also contribute to PRC2 function is not known. We characterized the target recognition specificity of the PRC2 active site and used the resultant data to screen for uncharacterized potential targets...
November 15, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29174924/the-output-of-protein-coding-genes-shifts-to-circular-rnas-when-the-pre-mrna-processing-machinery-is-limiting
#12
Dongming Liang, Deirdre C Tatomer, Zheng Luo, Huang Wu, Li Yang, Ling-Ling Chen, Sara Cherry, Jeremy E Wilusz
Many eukaryotic genes generate linear mRNAs and circular RNAs, but it is largely unknown how the ratio of linear to circular RNA is controlled or modulated. Using RNAi screening in Drosophila cells, we identify many core spliceosome and transcription termination factors that control the RNA outputs of reporter and endogenous genes. When spliceosome components were depleted or inhibited pharmacologically, the steady-state levels of circular RNAs increased while expression of their associated linear mRNAs concomitantly decreased...
November 9, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29153391/structure-of-a-thermostable-group-ii-intron-reverse-transcriptase-with-template-primer-and-its-functional-and-evolutionary-implications
#13
Jennifer L Stamos, Alfred M Lentzsch, Alan M Lambowitz
Bacterial group II intron reverse transcriptases (RTs) function in both intron mobility and RNA splicing and are evolutionary predecessors of retrotransposon, telomerase, and retroviral RTs as well as the spliceosomal protein Prp8 in eukaryotes. Here we determined a crystal structure of a full-length thermostable group II intron RT in complex with an RNA template-DNA primer duplex and incoming deoxynucleotide triphosphate (dNTP) at 3.0-Å resolution. We find that the binding of template-primer and key aspects of the RT active site are surprisingly different from retroviral RTs but remarkably similar to viral RNA-dependent RNA polymerases...
November 9, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29107538/hybrid-structure-of-the-raga-c-ragulator-mtorc1-activation-complex
#14
Ming-Yuan Su, Kyle L Morris, Do Jin Kim, Yangxue Fu, Rosalie Lawrence, Goran Stjepanovic, Roberto Zoncu, James H Hurley
The lysosomal membrane is the locus for sensing cellular nutrient levels, which are transduced to mTORC1 via the Rag GTPases and the Ragulator complex. The crystal structure of the five-subunit human Ragulator at 1.4 Å resolution was determined. Lamtor1 wraps around the other four subunits to stabilize the assembly. The Lamtor2:Lamtor3 dimer stacks upon Lamtor4:Lamtor5 to create a platform for Rag binding. Hydrogen-deuterium exchange was used to map the Rag binding site to the outer face of the Lamtor2:Lamtor3 dimer and to the N-terminal intrinsically disordered region of Lamtor1...
October 25, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29107537/base-resolution-mapping-reveals-distinct-m-1-a-methylome-in-nuclear-and-mitochondrial-encoded-transcripts
#15
Xiaoyu Li, Xushen Xiong, Meiling Zhang, Kun Wang, Ying Chen, Jun Zhou, Yuanhui Mao, Jia Lv, Danyang Yi, Xiao-Wei Chen, Chu Wang, Shu-Bing Qian, Chengqi Yi
Gene expression can be post-transcriptionally regulated via dynamic and reversible RNA modifications. N(1)-methyladenosine (m(1)A) is a recently identified mRNA modification; however, little is known about its precise location and biogenesis. Here, we develop a base-resolution m(1)A profiling method, based on m(1)A-induced misincorporation during reverse transcription, and report distinct classes of m(1)A methylome in the human transcriptome. m(1)A in 5' UTR, particularly those at the mRNA cap, associate with increased translation efficiency...
October 25, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29107536/the-unfolded-protein-response-and-cell-fate-control
#16
REVIEW
Claudio Hetz, Feroz R Papa
The secretory capacity of a cell is constantly challenged by physiological demands and pathological perturbations. To adjust and match the protein-folding capacity of the endoplasmic reticulum (ER) to changing secretory needs, cells employ a dynamic intracellular signaling pathway known as the unfolded protein response (UPR). Homeostatic activation of the UPR enforces adaptive programs that modulate and augment key aspects of the entire secretory pathway, whereas maladaptive UPR outputs trigger apoptosis. Here, we discuss recent advances into how the UPR integrates information about the intensity and duration of ER stress stimuli in order to control cell fate...
October 25, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29107535/genetically-encoded-tools-for-optical-dissection-of-the-mammalian-cell-cycle
#17
Asako Sakaue-Sawano, Masahiro Yo, Naoki Komatsu, Toru Hiratsuka, Takako Kogure, Tetsushi Hoshida, Naoki Goshima, Michiyuki Matsuda, Hiroyuki Miyoshi, Atsushi Miyawaki
Eukaryotic cells spend most of their life in interphase of the cell cycle. Understanding the rich diversity of metabolic and genomic regulation that occurs in interphase requires the demarcation of precise phase boundaries in situ. Here, we report the properties of two genetically encoded fluorescence sensors, Fucci(CA) and Fucci(SCA), which enable real-time monitoring of interphase and cell-cycle biology. We re-engineered the Cdt1-based sensor from the original Fucci system to respond to S phase-specific CUL4(Ddb1)-mediated ubiquitylation alone or in combination with SCF(Skp2)-mediated ubiquitylation...
October 25, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29107534/m-6-a-facilitates-eif4f-independent-mrna-translation
#18
Ryan A Coots, Xiao-Min Liu, Yuanhui Mao, Leiming Dong, Jun Zhou, Ji Wan, Xingqian Zhang, Shu-Bing Qian
In eukaryotic cells, protein synthesis typically begins with the binding of eIF4F to the 7-methylguanylate (m(7)G) cap found on the 5' end of the majority of mRNAs. Surprisingly, overall translational output remains robust under eIF4F inhibition. The broad spectrum of eIF4F-resistant translatomes is incompatible with cap-independent translation mediated by internal ribosome entry sites (IRESs). Here, we report that N(6)-methyladenosine (m(6)A) facilitates mRNA translation that is resistant to eIF4F inactivation...
October 23, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29220658/multi-omic-mitoprotease-profiling-defines-a-role-for-oct1p-in-coenzyme-q-production
#19
Mike T Veling, Andrew G Reidenbach, Elyse C Freiberger, Nicholas W Kwiecien, Paul D Hutchins, Michael J Drahnak, Adam Jochem, Arne Ulbrich, Matthew J P Rush, Jason D Russell, Joshua J Coon, David J Pagliarini
Mitoproteases are becoming recognized as key regulators of diverse mitochondrial functions, although their direct substrates are often difficult to discern. Through multi-omic profiling of diverse Saccharomyces cerevisiae mitoprotease deletion strains, we predicted numerous associations between mitoproteases and distinct mitochondrial processes. These include a strong association between the mitochondrial matrix octapeptidase Oct1p and coenzyme Q (CoQ) biosynthesis-a pathway essential for mitochondrial respiration...
December 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29220657/hnrnpk-recruits-pcgf3-5-prc1-to-the-xist-rna-b-repeat-to-establish-polycomb-mediated-chromosomal-silencing
#20
Greta Pintacuda, Guifeng Wei, Chloë Roustan, Burcu Anil Kirmizitas, Nicolae Solcan, Andrea Cerase, Alfredo Castello, Shabaz Mohammed, Benoît Moindrot, Tatyana B Nesterova, Neil Brockdorff
The Polycomb-repressive complexes PRC1 and PRC2 play a key role in chromosome silencing induced by the non-coding RNA Xist. Polycomb recruitment is initiated by the PCGF3/5-PRC1 complex, which catalyzes chromosome-wide H2A lysine 119 ubiquitylation, signaling recruitment of other PRC1 complexes, and PRC2. However, the molecular mechanism for PCGF3/5-PRC1 recruitment by Xist RNA is not understood. Here we define the Xist RNA Polycomb Interaction Domain (XR-PID), a 600 nt sequence encompassing the Xist B-repeat element...
December 7, 2017: Molecular Cell
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