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Molecular Cell

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https://www.readbyqxmd.com/read/28318821/snf2-family-protein-fft3-suppresses-nucleosome-turnover-to-promote-epigenetic-inheritance-and-proper-replication
#1
Nitika Taneja, Martin Zofall, Vanivilasini Balachandran, Gobi Thillainadesan, Tomoyasu Sugiyama, David Wheeler, Ming Zhou, Shiv I S Grewal
Heterochromatin can be epigenetically inherited in cis, leading to stable gene silencing. However, the mechanisms underlying heterochromatin inheritance remain unclear. Here, we identify Fft3, a fission yeast homolog of the mammalian SMARCAD1 SNF2 chromatin remodeler, as a factor uniquely required for heterochromatin inheritance, rather than for de novo assembly. Importantly, we find that Fft3 suppresses turnover of histones at heterochromatic loci to facilitate epigenetic transmission of heterochromatin in cycling cells...
March 8, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28318822/genome-wide-analysis-of-rna-polymerase-ii-termination-at-protein-coding-genes
#2
Carlo Baejen, Jessica Andreani, Phillipp Torkler, Sofia Battaglia, Bjoern Schwalb, Michael Lidschreiber, Kerstin C Maier, Andrea Boltendahl, Petra Rus, Stephanie Esslinger, Johannes Söding, Patrick Cramer
At the end of protein-coding genes, RNA polymerase (Pol) II undergoes a concerted transition that involves 3'-processing of the pre-mRNA and transcription termination. Here, we present a genome-wide analysis of the 3'-transition in budding yeast. We find that the 3'-transition globally requires the Pol II elongation factor Spt5 and factors involved in the recognition of the polyadenylation (pA) site and in endonucleolytic RNA cleavage. Pol II release from DNA occurs in a narrow termination window downstream of the pA site and requires the "torpedo" exonuclease Rat1 (XRN2 in human)...
March 6, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28216226/nbs1-phosphorylation-status-dictates-repair-choice-of-dysfunctional-telomeres
#3
Rekha Rai, Chunyi Hu, Cayla Broton, Yong Chen, Ming Lei, Sandy Chang
Telomeres employ TRF2 to protect chromosome ends from activating the DNA damage sensor MRE11-RAD50-NBS1 (MRN), thereby repressing ATM-dependent DNA damage checkpoint responses. How TRF2 prevents MRN activation at dysfunctional telomeres is unclear. Here, we show that the phosphorylation status of NBS1 determines the repair pathway choice of dysfunctional telomeres. The crystal structure of the TRF2-NBS1 complex at 3.0 Å resolution shows that the NBS1 429YQLSP433 motif interacts specifically with the TRF2(TRFH) domain...
February 8, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28190767/an-interaction-landscape-of-ubiquitin-signaling
#4
Xiaofei Zhang, Arne H Smits, Gabrielle B A van Tilburg, Pascal W T C Jansen, Matthew M Makowski, Huib Ovaa, Michiel Vermeulen
Intracellular signaling via the covalent attachment of different ubiquitin linkages to protein substrates is fundamental to many cellular processes. Although linkage-selective ubiquitin interactors have been studied on a case-by-case basis, proteome-wide analyses have not been conducted yet. Here, we present ubiquitin interactor affinity enrichment-mass spectrometry (UbIA-MS), a quantitative interaction proteomics method that makes use of chemically synthesized diubiquitin to enrich and identify ubiquitin linkage interactors from crude cell lysates...
January 25, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28306514/park2-depletion-connects-energy-and-oxidative-stress-to-pi3k-akt-activation-via-pten-s-nitrosylation
#5
Amit Gupta, Sara Anjomani-Virmouni, Nikos Koundouros, Maria Dimitriadi, Rayman Choo-Wing, Adamo Valle, Yuxiang Zheng, Yu-Hsin Chiu, Sameer Agnihotri, Gelareh Zadeh, John M Asara, Dimitrios Anastasiou, Mark J Arends, Lewis C Cantley, George Poulogiannis
PARK2 is a gene implicated in disease states with opposing responses in cell fate determination, yet its contribution in pro-survival signaling is largely unknown. Here we show that PARK2 is altered in over a third of all human cancers, and its depletion results in enhanced phosphatidylinositol 3-kinase/Akt (PI3K/Akt) activation and increased vulnerability to PI3K/Akt/mTOR inhibitors. PARK2 depletion contributes to AMPK-mediated activation of endothelial nitric oxide synthase (eNOS), enhanced levels of reactive oxygen species, and a concomitant increase in oxidized nitric oxide levels, thereby promoting the inhibition of PTEN by S-nitrosylation and ubiquitination...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28306513/tardigrades-use-intrinsically-disordered-proteins-to-survive-desiccation
#6
Thomas C Boothby, Hugo Tapia, Alexandra H Brozena, Samantha Piszkiewicz, Austin E Smith, Ilaria Giovannini, Lorena Rebecchi, Gary J Pielak, Doug Koshland, Bob Goldstein
Tardigrades are microscopic animals that survive a remarkable array of stresses, including desiccation. How tardigrades survive desiccation has remained a mystery for more than 250 years. Trehalose, a disaccharide essential for several organisms to survive drying, is detected at low levels or not at all in some tardigrade species, indicating that tardigrades possess potentially novel mechanisms for surviving desiccation. Here we show that tardigrade-specific intrinsically disordered proteins (TDPs) are essential for desiccation tolerance...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28306512/an-inflammatory-perspective-on-necroptosis
#7
REVIEW
Conor J Kearney, Seamus J Martin
Necroptosis (programmed necrosis) occurs in response to TNF, Fas, or TRAIL, as well as certain TLR ligands, when caspase activity required for apoptosis is blocked. Necroptosis is typically considered a highly pro-inflammatory mode of cell death, due to release of intracellular "danger signals" that promote inflammation. However, because most pro-necroptotic stimuli are intrinsically highly pro-inflammatory-due to their ability to initiate the synthesis of numerous cytokines and chemokines-the inflammatory consequences of necroptosis are complex...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28306511/phagebook-the-social-network
#8
Alexander P Hynes, Sylvain Moineau
Much like social networks are used to connect with friends or relatives, bacteria communicate with relatives through quorum sensing. Viruses, though, were thought to be asocial-until now. Erez et al. (2017) reveal that viruses are also sharing information with relatives.
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28306510/redox-control-of-mitochondrial-calcium-uptake
#9
Nicolas Demaurex, Manon Rosselin
Dong et al. (2017) establish how the mitochondrial Ca(2+) uniporter (MCU) integrates Ca(2+) and oxidative stress signals by identifying a cysteine residue that controls MCU channel activity, a mechanism causing mitochondrial Ca(2+) overload and cell death during oxidative stress.
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28306509/the-pten-parkin-axis-at-the-nexus-of-cancer-and-neurodegeneration
#10
Nathan T Ihle, Robert T Abraham
The PARK2 gene encodes an ubiquitin E3 ligase that is involved in mitochondrial homeostasis and linked to Parkinson's disease. In this issue, Gupta et al. (2017) demonstrate that PARK2 expression is frequently reduced in human cancers and that this alteration leads to dysregulated PI3K signaling.
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28306508/prokaryotic-argonaute-uses-an-all-in-one-mechanism-to-provide-host-defense
#11
Dipali G Sashital
In this issue, Swarts et al. (2017) discover that prokaryotic Argonaute proteins generate their own DNA guide strands through a newly characterized, unguided "chopping" activity. Double-stranded chopping products are selectively loaded onto Argonaute, enabling DNA-guided defense against foreign DNA.
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28306507/structural-and-molecular-mechanisms-of-cytokine-mediated-endocrine-resistance-in-human-breast-cancer-cells
#12
Joshua D Stender, Jerome C Nwachukwu, Irida Kastrati, Yohan Kim, Tobias Strid, Maayan Yakir, Sathish Srinivasan, Jason Nowak, Tina Izard, Erumbi S Rangarajan, Kathryn E Carlson, John A Katzenellenbogen, Xin-Qiu Yao, Barry J Grant, Hon S Leong, Chin-Yo Lin, Jonna Frasor, Kendall W Nettles, Christopher K Glass
Human breast cancers that exhibit high proportions of immune cells and elevated levels of pro-inflammatory cytokines predict poor prognosis. Here, we demonstrate that treatment of human MCF-7 breast cancer cells with pro-inflammatory cytokines results in ERα-dependent activation of gene expression and proliferation, in the absence of ligand or presence of 4OH-tamoxifen (TOT). Cytokine activation of ERα and endocrine resistance is dependent on phosphorylation of ERα at S305 in the hinge domain. Phosphorylation of S305 by IKKβ establishes an ERα cistrome that substantially overlaps with the estradiol (E2)-dependent ERα cistrome...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28306506/crystal-structure-of-the-minimal-cas9-from-campylobacter-jejuni-reveals-the-molecular-diversity-in-the-crispr-cas9-systems
#13
Mari Yamada, Yuto Watanabe, Jonathan S Gootenberg, Hisato Hirano, F Ann Ran, Takanori Nakane, Ryuichiro Ishitani, Feng Zhang, Hiroshi Nishimasu, Osamu Nureki
The RNA-guided endonuclease Cas9 generates a double-strand break at DNA target sites complementary to the guide RNA and has been harnessed for the development of a variety of new technologies, such as genome editing. Here, we report the crystal structures of Campylobacter jejuni Cas9 (CjCas9), one of the smallest Cas9 orthologs, in complex with an sgRNA and its target DNA. The structures provided insights into a minimal Cas9 scaffold and revealed the remarkable mechanistic diversity of the CRISPR-Cas9 systems...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28306505/identification-of-an-rna-polymerase-iii-regulator-linked-to-disease-associated-protein-aggregation
#14
Olga Sin, Tristan de Jong, Alejandro Mata-Cabana, Michelle Kudron, Mohamad Amr Zaini, Francesco A Aprile, Renée I Seinstra, Esther Stroo, Roméo Willinge Prins, Céline N Martineau, Hai Hui Wang, Wytse Hogewerf, Anne Steinhof, Erich E Wanker, Michele Vendruscolo, Cornelis F Calkhoven, Valerie Reinke, Victor Guryev, Ellen A A Nollen
Protein aggregation is associated with age-related neurodegenerative disorders, such as Alzheimer's and polyglutamine diseases. As a causal relationship between protein aggregation and neurodegeneration remains elusive, understanding the cellular mechanisms regulating protein aggregation will help develop future treatments. To identify such mechanisms, we conducted a forward genetic screen in a C. elegans model of polyglutamine aggregation and identified the protein MOAG-2/LIR-3 as a driver of protein aggregation...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28306504/targeting-of-polycomb-repressive-complex-2-to-rna-by-short-repeats-of-consecutive-guanines
#15
Xueyin Wang, Karen J Goodrich, Anne R Gooding, Haroon Naeem, Stuart Archer, Richard D Paucek, Daniel T Youmans, Thomas R Cech, Chen Davidovich
Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that trimethylates H3K27, a mark of repressed chromatin. Mammalian PRC2 binds RNA promiscuously, with thousands of target transcripts in vivo. But what does PRC2 recognize in these RNAs? Here we show that purified human PRC2 recognizes G > C,U ≫ A in single-stranded RNA and has a high affinity for folded guanine quadruplex (G4) structures but little binding to duplex RNAs. Importantly, G-tract motifs are significantly enriched among PRC2-binding transcripts in vivo...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28306503/phase-separation-of-c9orf72-dipeptide-repeats-perturbs-stress-granule-dynamics
#16
Steven Boeynaems, Elke Bogaert, Denes Kovacs, Albert Konijnenberg, Evy Timmerman, Alex Volkov, Mainak Guharoy, Mathias De Decker, Tom Jaspers, Veronica H Ryan, Abigail M Janke, Pieter Baatsen, Thomas Vercruysse, Regina-Maria Kolaitis, Dirk Daelemans, J Paul Taylor, Nancy Kedersha, Paul Anderson, Francis Impens, Frank Sobott, Joost Schymkowitz, Frederic Rousseau, Nicolas L Fawzi, Wim Robberecht, Philip Van Damme, Peter Tompa, Ludo Van Den Bosch
Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a cornerstone of ALS/FTLD pathogenesis. Polar residues (tyrosine and glutamine) have been previously demonstrated to be critical for phase separation of ALS-linked stress granule proteins. We now identify an active role for arginine-rich domains in these phase separations...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28306502/pacer-mediates-the-function-of-class-iii-pi3k-and-hops-complexes-in-autophagosome-maturation-by-engaging-stx17
#17
Xiawei Cheng, Xiuling Ma, Xianming Ding, Lin Li, Xiao Jiang, Zhirong Shen, She Chen, Wei Liu, Weihua Gong, Qiming Sun
Class III PI3-kinase (PI3KC3) is essential for autophagy initiation, but whether PI3KC3 participates in other steps of autophagy remains unknown. The HOPS complex mediates the fusion of intracellular vesicles to lysosome, but how HOPS specifically tethers autophagosome to lysosome remains elusive. Here, we report Pacer (protein associated with UVRAG as autophagy enhancer) as a regulator of autophagy. Pacer localizes to autophagic structures and positively regulates autophagosome maturation. Mechanistically, Pacer antagonizes Rubicon to stimulate Vps34 kinase activity...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28286024/erk-induced-activation-of-tcf-family-of-srf-cofactors-initiates-a-chromatin-modification-cascade-associated-with-transcription
#18
Cyril Esnault, Francesco Gualdrini, Stuart Horswell, Gavin Kelly, Aengus Stewart, Phil East, Nik Matthews, Richard Treisman
We investigated the relationship among ERK signaling, histone modifications, and transcription factor activity, focusing on the ERK-regulated ternary complex factor family of SRF partner proteins. In MEFs, activation of ERK by TPA stimulation induced a common pattern of H3K9acS10ph, H4K16ac, H3K27ac, H3K9acK14ac, and H3K4me3 at hundreds of transcription start site (TSS) regions and remote regulatory sites. The magnitude of the increase in histone modification correlated well with changes in transcription. H3K9acS10ph preceded the other modifications...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28262506/autonomous-generation-and-loading-of-dna-guides-by-bacterial-argonaute
#19
Daan C Swarts, Malwina Szczepaniak, Gang Sheng, Stanley D Chandradoss, Yifan Zhu, Elizabeth M Timmers, Yong Zhang, Hongtu Zhao, Jizhong Lou, Yanli Wang, Chirlmin Joo, John van der Oost
Several prokaryotic Argonaute proteins (pAgos) utilize small DNA guides to mediate host defense by targeting invading DNA complementary to the DNA guide. It is unknown how these DNA guides are being generated and loaded onto pAgo. Here, we demonstrate that guide-free Argonaute from Thermus thermophilus (TtAgo) can degrade double-stranded DNA (dsDNA), thereby generating small dsDNA fragments that subsequently are loaded onto TtAgo. Combining single-molecule fluorescence, molecular dynamic simulations, and structural studies, we show that TtAgo loads dsDNA molecules with a preference toward a deoxyguanosine on the passenger strand at the position opposite to the 5' end of the guide strand...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28262505/distinct-roles-of-brd2-and-brd4-in-potentiating-the-transcriptional-program-for-th17-cell-differentiation
#20
Ka Lung Cheung, Fan Zhang, Anbalagan Jaganathan, Rajal Sharma, Qiang Zhang, Tsuyoshi Konuma, Tong Shen, June-Yong Lee, Chunyan Ren, Chih-Hung Chen, Geming Lu, Matthew R Olson, Weijia Zhang, Mark H Kaplan, Dan R Littman, Martin J Walsh, Huabao Xiong, Lei Zeng, Ming-Ming Zhou
The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf...
March 16, 2017: Molecular Cell
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