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Molecular Cell

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https://www.readbyqxmd.com/read/28781237/heterogeneity-of-stop-codon-readthrough-in-single-bacterial-cells-and-implications-for-population-fitness
#1
Yongqiang Fan, Christopher R Evans, Karl W Barber, Kinshuk Banerjee, Kalyn J Weiss, William Margolin, Oleg A Igoshin, Jesse Rinehart, Jiqiang Ling
Gene expression noise (heterogeneity) leads to phenotypic diversity among isogenic individual cells. Our current understanding of gene expression noise is mostly limited to transcription, as separating translational noise from transcriptional noise has been challenging. It also remains unclear how translational heterogeneity originates. Using a transcription-normalized reporter system, we discovered that stop codon readthrough is heterogeneous among single cells, and individual cells with higher UGA readthrough grow faster from stationary phase...
August 1, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28803779/chromodomain-protein-cdyl-acts-as-a-crotonyl-coa-hydratase-to-regulate-histone-crotonylation-and-spermatogenesis
#2
Shumeng Liu, Huajing Yu, Yongqing Liu, Xinhua Liu, Yu Zhang, Chen Bu, Shuai Yuan, Zhe Chen, Guojia Xie, Wanjin Li, Bosen Xu, Jianguo Yang, Lin He, Tong Jin, Yundong Xiong, Luyang Sun, Xiaohui Liu, Chunsheng Han, Zhongyi Cheng, Jing Liang, Yongfeng Shang
Lysine crotonylation (Kcr) is a newly identified histone modification that is associated with active transcription in mammalian cells. Here we report that the chromodomain Y-like transcription corepressor CDYL negatively regulates histone Kcr by acting as a crotonyl-CoA hydratase to convert crotonyl-CoA to β-hydroxybutyryl-CoA. We showed that the negative regulation of histone Kcr by CDYL is intrinsically linked to its transcription repression activity and functionally implemented in the reactivation of sex chromosome-linked genes in round spermatids and genome-wide histone replacement in elongating spermatids...
July 29, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28803776/mechanism-of-enzyme-repair-by-the-aaa-chaperone-rubisco-activase
#3
Javaid Y Bhat, Goran Miličić, Gabriel Thieulin-Pardo, Andreas Bracher, Andrew Maxwell, Susanne Ciniawsky, Oliver Mueller-Cajar, John R Engen, F Ulrich Hartl, Petra Wendler, Manajit Hayer-Hartl
How AAA+ chaperones conformationally remodel specific target proteins in an ATP-dependent manner is not well understood. Here, we investigated the mechanism of the AAA+ protein Rubisco activase (Rca) in metabolic repair of the photosynthetic enzyme Rubisco, a complex of eight large (RbcL) and eight small (RbcS) subunits containing eight catalytic sites. Rubisco is prone to inhibition by tight-binding sugar phosphates, whose removal is catalyzed by Rca. We engineered a stable Rca hexamer ring and analyzed its functional interaction with Rubisco...
July 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28757209/smarcal1-mediated-fork-reversal-triggers-mre11-dependent-degradation-of-nascent-dna-in-the-absence-of-brca2-and-stable-rad51-nucleofilaments
#4
Arun Mouli Kolinjivadi, Vincenzo Sannino, Anna De Antoni, Karina Zadorozhny, Mairi Kilkenny, Hervé Técher, Giorgio Baldi, Rong Shen, Alberto Ciccia, Luca Pellegrini, Lumir Krejci, Vincenzo Costanzo
Brca2 deficiency causes Mre11-dependent degradation of nascent DNA at stalled forks, leading to cell lethality. To understand the molecular mechanisms underlying this process, we isolated Xenopus laevis Brca2. We demonstrated that Brca2 protein prevents single-stranded DNA gap accumulation at replication fork junctions and behind them by promoting Rad51 binding to replicating DNA. Without Brca2, forks with persistent gaps are converted by Smarcal1 into reversed forks, triggering extensive Mre11-dependent nascent DNA degradation...
July 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28820965/systematic-identification-of-mcu-modulators-by-orthogonal-interspecies-chemical-screening
#5
Daniela M Arduino, Jennifer Wettmarshausen, Horia Vais, Paloma Navas-Navarro, Yiming Cheng, Anja Leimpek, Zhongming Ma, Alba Delrio-Lorenzo, Andrea Giordano, Cecilia Garcia-Perez, Guillaume Médard, Bernhard Kuster, Javier García-Sancho, Dejana Mokranjac, J Kevin Foskett, M Teresa Alonso, Fabiana Perocchi
The mitochondrial calcium uniporter complex is essential for calcium (Ca(2+)) uptake into mitochondria of all mammalian tissues, where it regulates bioenergetics, cell death, and Ca(2+) signal transduction. Despite its involvement in several human diseases, we currently lack pharmacological agents for targeting uniporter activity. Here we introduce a high-throughput assay that selects for human MCU-specific small-molecule modulators in primary drug screens. Using isolated yeast mitochondria, reconstituted with human MCU, its essential regulator EMRE, and aequorin, and exploiting a D-lactate- and mannitol/sucrose-based bioenergetic shunt that greatly minimizes false-positive hits, we identify mitoxantrone out of more than 600 clinically approved drugs as a direct selective inhibitor of human MCU...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28820964/modulating-the-modulator-regulation-of-protein-methylation-by-nitric-oxide
#6
Lucas Frungillo, Steven H Spoel
Protein methylation is an important modulator of signal transduction pathways, but methyltransferases themselves may also be modulated. Hu et al. (2017) demonstrate in this issue of Molecular Cell that S-nitrosylation selectively modulates enzymatic activity of a protein arginine methyltransferase vital to abiotic stress tolerance.
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28803781/myc-regulates-chromatin-decompaction-and-nuclear-architecture-during-b-cell-activation
#7
Kyong-Rim Kieffer-Kwon, Keisuke Nimura, Suhas S P Rao, Jianliang Xu, Seolkyoung Jung, Aleksandra Pekowska, Marei Dose, Evan Stevens, Ewy Mathe, Peng Dong, Su-Chen Huang, Maria Aurelia Ricci, Laura Baranello, Ying Zheng, Francesco Tomassoni Ardori, Wolfgang Resch, Diana Stavreva, Steevenson Nelson, Michael McAndrew, Adriel Casellas, Elizabeth Finn, Charles Gregory, Brian Glenn St Hilaire, Steven M Johnson, Wendy Dubois, Maria Pia Cosma, Eric Batchelor, David Levens, Robert D Phair, Tom Misteli, Lino Tessarollo, Gordon Hager, Melike Lakadamyali, Zhe Liu, Monique Floer, Hari Shroff, Erez Lieberman Aiden, Rafael Casellas
50 years ago, Vincent Allfrey and colleagues discovered that lymphocyte activation triggers massive acetylation of chromatin. However, the molecular mechanisms driving epigenetic accessibility are still unknown. We here show that stimulated lymphocytes decondense chromatin by three differentially regulated steps. First, chromatin is repositioned away from the nuclear periphery in response to global acetylation. Second, histone nanodomain clusters decompact into mononucleosome fibers through a mechanism that requires Myc and continual energy input...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28803780/methylation-of-dna-ligase-1-by-g9a-glp-recruits-uhrf1-to-replicating-dna-and-regulates-dna-methylation
#8
Laure Ferry, Alexandra Fournier, Takeshi Tsusaka, Guillaume Adelmant, Tadahiro Shimazu, Shohei Matano, Olivier Kirsh, Rachel Amouroux, Naoshi Dohmae, Takehiro Suzuki, Guillaume J Filion, Wen Deng, Maud de Dieuleveult, Lauriane Fritsch, Srikanth Kudithipudi, Albert Jeltsch, Heinrich Leonhardt, Petra Hajkova, Jarrod A Marto, Kyohei Arita, Yoichi Shinkai, Pierre-Antoine Defossez
DNA methylation is an essential epigenetic mark in mammals that has to be re-established after each round of DNA replication. The protein UHRF1 is essential for this process; it has been proposed that the protein targets newly replicated DNA by cooperatively binding hemi-methylated DNA and H3K9me2/3, but this model leaves a number of questions unanswered. Here, we present evidence for a direct recruitment of UHRF1 by the replication machinery via DNA ligase 1 (LIG1). A histone H3K9-like mimic within LIG1 is methylated by G9a and GLP and, compared with H3K9me2/3, more avidly binds UHRF1...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28803778/an-unstable-singularity-underlies-stochastic-phasing-of-the-circadian-clock-in-individual-cyanobacterial-cells
#9
Siting Gan, Erin K O'Shea
The endogenous circadian clock synchronizes with environmental time by appropriately resetting its phase in response to external cues. Of note, some resetting stimuli induce attenuated oscillations of clock output, which has been observed at the population-level in several organisms and in studies of individual humans. To investigate what is happening in individual cellular clocks, we studied the unicellular cyanobacterium S. elongatus. By measuring its phase-resetting responses to temperature changes, we found that population-level arrhythmicity occurs when certain perturbations cause stochastic phases of oscillations in individual cells...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28803777/paraoxonase-2-facilitates-pancreatic-cancer-growth-and-metastasis-by-stimulating-glut1-mediated-glucose-transport
#10
Arvindhan Nagarajan, Shaillay Kumar Dogra, Lisha Sun, Neeru Gandotra, Thuy Ho, Guoping Cai, Gary Cline, Priti Kumar, Robert A Cowles, Narendra Wajapeyee
Metabolic deregulation is a hallmark of human cancers, and the glycolytic and glutamine metabolism pathways were shown to be deregulated in pancreatic ductal adenocarcinoma (PDAC). To identify new metabolic regulators of PDAC tumor growth and metastasis, we systematically knocked down metabolic genes that were overexpressed in human PDAC tumor samples using short hairpin RNAs. We found that p53 transcriptionally represses paraoxonase 2 (PON2), which regulates GLUT1-mediated glucose transport via stomatin. The loss of PON2 initiates the cellular starvation response and activates AMP-activated protein kinase (AMPK)...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28781236/structural-variation-of-type-i-f-crispr-rna-guided-dna-surveillance
#11
Patrick Pausch, Hanna Müller-Esparza, Daniel Gleditzsch, Florian Altegoer, Lennart Randau, Gert Bange
CRISPR-Cas systems are prokaryotic immune systems against invading nucleic acids. Type I CRISPR-Cas systems employ highly diverse, multi-subunit surveillance Cascade complexes that facilitate duplex formation between crRNA and complementary target DNA for R-loop formation, retention, and DNA degradation by the subsequently recruited nuclease Cas3. Typically, the large subunit recognizes bona fide targets through the PAM (protospacer adjacent motif), and the small subunit guides the non-target DNA strand. Here, we present the Apo- and target-DNA-bound structures of the I-Fv (type I-F variant) Cascade lacking the small and large subunits...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28781235/regulation-of-hetdna-length-during-mitotic-double-strand-break-repair-in-yeast
#12
Xiaoge Guo, Yee Fang Hum, Kevin Lehner, Sue Jinks-Robertson
Heteroduplex DNA (hetDNA) is a key molecular intermediate during the repair of mitotic double-strand breaks by homologous recombination, but its relationship to 5' end resection and/or 3' end extension is poorly understood. In the current study, we examined how perturbations in these processes affect the hetDNA profile associated with repair of a defined double-strand break (DSB) by the synthesis-dependent strand-annealing (SDSA) pathway. Loss of either the Exo1 or Sgs1 long-range resection pathway significantly shortened hetDNA, suggesting that these pathways normally collaborate during DSB repair...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28781234/structural-basis-for-the-canonical-and-non-canonical-pam-recognition-by-crispr-cpf1
#13
Takashi Yamano, Bernd Zetsche, Ryuichiro Ishitani, Feng Zhang, Hiroshi Nishimasu, Osamu Nureki
The RNA-guided Cpf1 (also known as Cas12a) nuclease associates with a CRISPR RNA (crRNA) and cleaves the double-stranded DNA target complementary to the crRNA guide. The two Cpf1 orthologs from Acidaminococcus sp. (AsCpf1) and Lachnospiraceae bacterium (LbCpf1) have been harnessed for eukaryotic genome editing. Cpf1 requires a specific nucleotide sequence, called a protospacer adjacent motif (PAM), for target recognition. Besides the canonical TTTV PAM, Cpf1 recognizes suboptimal C-containing PAMs. Here, we report four crystal structures of LbCpf1 in complex with the crRNA and its target DNA containing either TTTA, TCTA, TCCA, or CCCA as the PAM...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28781233/phospho-h1-decorates-the-inter-chromatid-axis-and-is-evicted-along-with-shugoshin-by-set-during-mitosis
#14
Swathi Krishnan, Arne H Smits, Michiel Vermeulen, Danny Reinberg
Precise control of sister chromatid separation during mitosis is pivotal to maintaining genomic integrity. Yet, the regulatory mechanisms involved are not well understood. Remarkably, we discovered that linker histone H1 phosphorylated at S/T18 decorated the inter-chromatid axial DNA on mitotic chromosomes. Sister chromatid resolution during mitosis required the eviction of such H1S/T18ph by the chaperone SET, with this process being independent of and most likely downstream of arm-cohesin dissociation. SET also directed the disassembly of Shugoshins in a polo-like kinase 1-augmented manner, aiding centromere resolution...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28781232/multivalent-recruitment-of-human-argonaute-by-gw182
#15
Elad Elkayam, Christopher R Faehnle, Marjorie Morales, Jingchuan Sun, Huilin Li, Leemor Joshua-Tor
In miRNA-mediated gene silencing, the physical interaction between human Argonaute (hAgo) and GW182 (hGW182) is essential for facilitating the downstream silencing of the targeted mRNA. GW182 can interact with hAgo via three of the GW/WG repeats in its Argonaute-binding domain: motif-1, motif-2, and the hook motif. The structure of hAgo1 in complex with the hook motif of hGW182 reveals a "gate"-like interaction that is critical for GW182 docking into one of hAgo1's tryptophan-binding pockets. We show that hAgo1 and hAgo2 have a single GW182-binding site and that miRNA binding increases hAgo's affinity to GW182...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28757210/introns-protect-eukaryotic-genomes-from-transcription-associated-genetic-instability
#16
Amandine Bonnet, Ana R Grosso, Abdessamad Elkaoutari, Emeline Coleno, Adrien Presle, Sreerama C Sridhara, Guilhem Janbon, Vincent Géli, Sérgio F de Almeida, Benoit Palancade
Transcription is a source of genetic instability that can notably result from the formation of genotoxic DNA:RNA hybrids, or R-loops, between the nascent mRNA and its template. Here we report an unexpected function for introns in counteracting R-loop accumulation in eukaryotic genomes. Deletion of endogenous introns increases R-loop formation, while insertion of an intron into an intronless gene suppresses R-loop accumulation and its deleterious impact on transcription and recombination in yeast. Recruitment of the spliceosome onto the mRNA, but not splicing per se, is shown to be critical to attenuate R-loop formation and transcription-associated genetic instability...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28757206/nitric-oxide-regulates-protein-methylation-during-stress-responses-in-plants
#17
Jiliang Hu, Huanjie Yang, Jinye Mu, Tiancong Lu, Juli Peng, Xian Deng, Zhaosheng Kong, Shilai Bao, Xiaofeng Cao, Jianru Zuo
Methylation and nitric oxide (NO)-based S-nitrosylation are highly conserved protein posttranslational modifications that regulate diverse biological processes. In higher eukaryotes, PRMT5 catalyzes Arg symmetric dimethylation, including key components of the spliceosome. The Arabidopsis prmt5 mutant shows severe developmental defects and impaired stress responses. However, little is known about the mechanisms regulating the PRMT5 activity. Here, we report that NO positively regulates the PRMT5 activity through S-nitrosylation at Cys-125 during stress responses...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28735899/mot1-ino80c-and-nc2-function-coordinately-to-regulate-pervasive-transcription-in-yeast-and-mammals
#18
Yong Xue, Suman K Pradhan, Fei Sun, Constantinos Chronis, Nancy Tran, Trent Su, Christopher Van, Ajay Vashisht, James Wohlschlegel, Craig L Peterson, H T Marc Timmers, Siavash K Kurdistani, Michael F Carey
Pervasive transcription initiates from cryptic promoters and is observed in eukaryotes ranging from yeast to mammals. The Set2-Rpd3 regulatory system prevents cryptic promoter function within expressed genes. However, conserved systems that control pervasive transcription within intergenic regions have not been well established. Here we show that Mot1, Ino80 chromatin remodeling complex (Ino80C), and NC2 co-localize on chromatin and coordinately suppress pervasive transcription in S. cerevisiae and murine embryonic stem cells (mESCs)...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28689662/activation-of-the-unfolded-protein-response-by-lipid-bilayer-stress
#19
Kristina Halbleib, Kristina Pesek, Roberto Covino, Harald F Hofbauer, Dorith Wunnicke, Inga Hänelt, Gerhard Hummer, Robert Ernst
The unfolded protein response (UPR) is a conserved homeostatic program that is activated by misfolded proteins in the lumen of the endoplasmic reticulum (ER). Recently, it became evident that aberrant lipid compositions of the ER membrane, referred to as lipid bilayer stress, are equally potent in activating the UPR. The underlying molecular mechanism, however, remained unclear. We show that the most conserved transducer of ER stress, Ire1, uses an amphipathic helix (AH) to sense membrane aberrancies and control UPR activity...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28777948/hexim1-has-different-functions-within-different-rna-protein-complexes
#20
Olivier Bensaude
In this issue of Molecular Cell, Morchikh et al. (2017) describe a new ribonuclear complex built around HEXIM1 and the long non-coding RNA NEAT1. This complex regulates the innate immune response to DNA viruses and is distinct from the HEXIM1-7SK RNA complex that regulates transcription elongation.
August 3, 2017: Molecular Cell
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