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Molecular Cell

Xiang Li, Chu-Xiao Liu, Wei Xue, Yang Zhang, Shan Jiang, Qing-Fei Yin, Jia Wei, Run-Wen Yao, Li Yang, Ling-Ling Chen
Circular RNAs (circRNAs) generated via back-splicing are enhanced by flanking complementary sequences. Expression levels of circRNAs vary under different conditions, suggesting participation of protein factors in their biogenesis. Using genome-wide siRNA screening that targets all human unique genes and an efficient circRNA expression reporter, we identify double-stranded RNA-binding domain containing immune factors NF90/NF110 as key regulators in circRNA biogenesis. NF90/NF110 promote circRNA production in the nucleus by associating with intronic RNA pairs juxtaposing the circRNA-forming exon(s); they also interact with mature circRNAs in the cytoplasm...
June 12, 2017: Molecular Cell
Zhen Shi, Kotaro Fujii, Kyle M Kovary, Naomi R Genuth, Hannes L Röst, Mary N Teruel, Maria Barna
Emerging studies have linked the ribosome to more selective control of gene regulation. However, an outstanding question is whether ribosome heterogeneity at the level of core ribosomal proteins (RPs) exists and enables ribosomes to preferentially translate specific mRNAs genome-wide. Here, we measured the absolute abundance of RPs in translating ribosomes and profiled transcripts that are enriched or depleted from select subsets of ribosomes within embryonic stem cells. We find that heterogeneity in RP composition endows ribosomes with differential selectivity for translating subpools of transcripts, including those controlling metabolism, cell cycle, and development...
June 7, 2017: Molecular Cell
Y Grace Chen, Myoungjoo V Kim, Xingqi Chen, Pedro J Batista, Saeko Aoyama, Jeremy E Wilusz, Akiko Iwasaki, Howard Y Chang
Circular RNAs (circRNAs) are single-stranded RNAs that are joined head to tail with largely unknown functions. Here we show that transfection of purified in vitro generated circRNA into mammalian cells led to potent induction of innate immunity genes and confers protection against viral infection. The nucleic acid sensor RIG-I is necessary to sense foreign circRNA, and RIG-I and foreign circRNA co-aggregate in cytoplasmic foci. CircRNA activation of innate immunity is independent of a 5' triphosphate, double-stranded RNA structure, or the primary sequence of the foreign circRNA...
June 7, 2017: Molecular Cell
Srirupa Roy, Andrew M Leidal, Jordan Ye, Sabrina M Ronen, Jayanta Debnath
Autophagy traditionally sustains metabolism in stressed cells by promoting intracellular catabolism and nutrient recycling. Here, we demonstrate that in response to stresses requiring increased glycolytic demand, the core autophagy machinery also facilitates glucose uptake and glycolytic flux by promoting cell surface expression of the glucose transporter GLUT1/Slc2a1. During metabolic stress, LC3(+) autophagic compartments bind and sequester the RabGAP protein TBC1D5 away from its inhibitory interactions with the retromer complex, thereby enabling retromer recruitment to endosome membranes and GLUT1 plasma membrane translocation...
June 6, 2017: Molecular Cell
Hiroshi Nishimasu, Takashi Yamano, Linyi Gao, Feng Zhang, Ryuichiro Ishitani, Osamu Nureki
The RNA-guided Cpf1 nuclease cleaves double-stranded DNA targets complementary to the CRISPR RNA (crRNA), and it has been harnessed for genome editing technologies. Recently, Acidaminococcus sp. BV3L6 (AsCpf1) was engineered to recognize altered DNA sequences as the protospacer adjacent motif (PAM), thereby expanding the target range of Cpf1-mediated genome editing. Whereas wild-type AsCpf1 recognizes the TTTV PAM, the RVR (S542R/K548V/N552R) and RR (S542R/K607R) variants can efficiently recognize the TATV and TYCV PAMs, respectively...
June 6, 2017: Molecular Cell
Olga M Mazina, Havva Keskin, Kritika Hanamshet, Francesca Storici, Alexander V Mazin
RNA can serve as a template for DNA double-strand break repair in yeast cells, and Rad52, a member of the homologous recombination pathway, emerged as an important player in this process. However, the exact mechanism of how Rad52 contributes to RNA-dependent DSB repair remained unknown. Here, we report an unanticipated activity of yeast and human Rad52: inverse strand exchange, in which Rad52 forms a complex with dsDNA and promotes strand exchange with homologous ssRNA or ssDNA. We show that in eukaryotes, inverse strand exchange between homologous dsDNA and RNA is a distinctive activity of Rad52; neither Rad51 recombinase nor the yeast Rad52 paralog Rad59 has this activity...
June 5, 2017: Molecular Cell
Hui Yang, Dinshaw J Patel
Prokaryotic CRISPR-Cas adaptive immune systems utilize sequence-specific RNA-guided endonucleases to defend against infection by viruses, bacteriophages, and mobile elements, while these foreign genetic elements evolve diverse anti-CRISPR proteins to overcome the CRISPR-Cas-mediated defense of the host. Recently, AcrIIA2 and AcrIIA4, encoded by Listeria monocytogene prophages, were shown to block the endonuclease activity of type II-A Streptococcus pyogene Cas9 (SpyCas9). We now report the crystal structure of AcrIIA4 in complex with single-guide RNA-bound SpyCas9, thereby establishing that AcrIIA4 preferentially targets critical residues essential for PAM duplex recognition, as well as blocks target DNA access to key catalytic residues lining the RuvC pocket...
June 2, 2017: Molecular Cell
Robert Glyde, Fuzhou Ye, Vidya Chandran Darbari, Nan Zhang, Martin Buck, Xiaodong Zhang
Gene transcription is carried out by RNA polymerases (RNAPs). For transcription to occur, the closed promoter complex (RPc), where DNA is double stranded, must isomerize into an open promoter complex (RPo), where the DNA is melted out into a transcription bubble and the single-stranded template DNA is delivered to the RNAP active site. Using a bacterial RNAP containing the alternative σ(54) factor and cryoelectron microscopy, we determined structures of RPc and the activator-bound intermediate complex en route to RPo at 3...
May 20, 2017: Molecular Cell
Andrew N Blackford, Stephen P Jackson
In vertebrate cells, the DNA damage response is controlled by three related kinases: ATM, ATR, and DNA-PK. It has been 20 years since the cloning of ATR, the last of the three to be identified. During this time, our understanding of how these kinases regulate DNA repair and associated events has grown profoundly, although major questions remain unanswered. Here, we provide a historical perspective of their discovery and discuss their established functions in sensing and responding to genotoxic stress. We also highlight what is known regarding their structural similarities and common mechanisms of regulation, as well as emerging non-canonical roles and how our knowledge of ATM, ATR, and DNA-PK is being translated to benefit human health...
June 15, 2017: Molecular Cell
Daniel Garcia, Reuben J Shaw
AMPK is a highly conserved master regulator of metabolism, which restores energy balance during metabolic stress both at the cellular and physiological levels. The identification of numerous AMPK targets has helped explain how AMPK restores energy homeostasis. Recent advancements illustrate novel mechanisms of AMPK regulation, including changes in subcellular localization and phosphorylation by non-canonical upstream kinases. Notably, the therapeutic potential of AMPK is widely recognized and heavily pursued for treatment of metabolic diseases such as diabetes, but also obesity, inflammation, and cancer...
June 15, 2017: Molecular Cell
Rafaela Bagur, György Hajnóczky
Ca(2+) is a ubiquitous intracellular messenger that controls diverse cellular functions but can become toxic and cause cell death. Selective control of specific targets depends on spatiotemporal patterning of the calcium signal and decoding it by multiple, tunable, and often strategically positioned Ca(2+)-sensing elements. Ca(2+) is detected by specialized motifs on proteins that have been biochemically characterized decades ago. However, the field of Ca(2+) sensing has been reenergized by recent progress in fluorescent technology, genetics, and cryo-EM...
June 15, 2017: Molecular Cell
Mircea Ivan, William G Kaelin
The EGLN (also called PHD) prolyl hydroxylase enzymes and their canonical targets, the HIFα subunits, represent the core of an ancient oxygen-monitoring machinery used by metazoans. In this review, we highlight recent progress in understanding the overlapping versus specific roles of EGLN enzymes and HIF isoforms and discuss how feedback loops based on recently identified noncoding RNAs introduce additional layers of complexity to the hypoxic response. Based on novel interactions identified upstream and downstream of EGLNs, an integrated network connecting oxygen-sensing functions to metabolic and signaling pathways is gradually emerging with broad therapeutic implications...
June 15, 2017: Molecular Cell
Ashley E Frakes, Andrew Dillin
Life is stressful. Organisms are repeatedly exposed to stressors that disrupt protein homeostasis (proteostasis), resulting in protein misfolding and aggregation. To sense and respond to proteotoxic perturbations, cells have evolved compartment-specific stress responses, such as the unfolded protein response of the endoplasmic reticulum (UPR(ER)). However, UPR(ER) function is impaired with age, which, we propose, creates a permissive environment for protein aggregation, unresolved ER stress, and chronic inflammation...
June 15, 2017: Molecular Cell
Kate M Franz, Jonathan C Kagan
Infections can cause a multitude of stresses on the host and microbe. To detect potential infections, the mammalian immune system utilizes several families of pattern recognition receptors, which survey the intracellular and extracellular environments for microbial products. Members of each receptor family induce antimicrobial effector responses, which include inflammatory cytokine or interferon expression, downregulation of protein synthesis, or host cell death. In this review, we discuss the benefits of each of these innate immune responses...
June 15, 2017: Molecular Cell
Luis Toledo, Kai John Neelsen, Jiri Lukas
Proliferating cells rely on the so-called DNA replication checkpoint to ensure orderly completion of genome duplication, and its malfunction may lead to catastrophic genome disruption, including unscheduled firing of replication origins, stalling and collapse of replication forks, massive DNA breakage, and, ultimately, cell death. Despite many years of intensive research into the molecular underpinnings of the eukaryotic replication checkpoint, the mechanisms underlying the dismal consequences of its failure remain enigmatic...
June 15, 2017: Molecular Cell
Elizabeth A Libby, Jonathan Dworkin
How do neighboring bacterial biofilms sense and communicate with each other? In a recent paper, Liu et al. (2017) demonstrate how electrical signaling allows communication of metabolic states between adjacent B. subtilis biofilms, providing a possible generalizable mechanism for communication in multispecies biofilms with interdependent metabolism.
June 15, 2017: Molecular Cell
Benjamin P Garfinkel, Gökhan S Hotamisligil
A new mechanism linking ER dysfunction to metabolic inflammation is discovered in a recent study by Shan et al. (2017), which demonstrated ER stress-induced rewiring of adipose tissue macrophage polarization by IRE1α activation, leading to impaired systemic glucose homeostasis.
June 15, 2017: Molecular Cell
Jan Bednar, Isabel Garcia-Saez, Ramachandran Boopathi, Amber R Cutter, Gabor Papai, Anna Reymer, Sajad H Syed, Imtiaz Nisar Lone, Ognyan Tonchev, Corinne Crucifix, Hervé Menoni, Christophe Papin, Dimitrios A Skoufias, Hitoshi Kurumizaka, Richard Lavery, Ali Hamiche, Jeffrey J Hayes, Patrick Schultz, Dimitar Angelov, Carlo Petosa, Stefan Dimitrov
No abstract text is available yet for this article.
June 1, 2017: Molecular Cell
Neha Puri, A Wali Karzai
The AAA+ Lon protease is conserved from bacteria to humans, performs crucial roles in protein homeostasis, and is implicated in bacterial pathogenesis and human disease. We investigated how Lon selectively degrades specific substrates among a diverse array of potential targets. We report the discovery of HspQ as a new Lon substrate, unique specificity-enhancing factor, and potent allosteric activator. Lon recognizes HspQ via a C-terminal degron, whose precise presentation, in synergy with multipartite contacts with the native core of HspQ, is required for allosteric Lon activation...
June 1, 2017: Molecular Cell
Stefano Di Marco, Zdenka Hasanova, Radhakrishnan Kanagaraj, Nagaraja Chappidi, Veronika Altmannova, Shruti Menon, Hana Sedlackova, Jana Langhoff, Kalpana Surendranath, Daniela Hühn, Rahul Bhowmick, Victoria Marini, Stefano Ferrari, Ian D Hickson, Lumir Krejci, Pavel Janscak
The MUS81-EME1 endonuclease cleaves late replication intermediates at common fragile sites (CFSs) during early mitosis to trigger DNA-repair synthesis that ensures faithful chromosome segregation. Here, we show that these DNA transactions are promoted by RECQ5 DNA helicase in a manner dependent on its Ser727 phosphorylation by CDK1. Upon replication stress, RECQ5 associates with CFSs in early mitosis through its physical interaction with MUS81 and promotes MUS81-dependent mitotic DNA synthesis. RECQ5 depletion or mutational inactivation of its ATP-binding site, RAD51-interacting domain, or phosphorylation site causes excessive binding of RAD51 to CFS loci and impairs CFS expression...
June 1, 2017: Molecular Cell
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