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Molecular Cell

Damián Gatica, Guowu Hu, Xu Liu, Nannan Zhang, Peter R Williamson, Daniel J Klionsky
Macroautophagy/autophagy is a key catabolic recycling pathway that requires fine-tuned regulation to prevent pathologies and preserve homeostasis. Here, we report a new post-transcriptional pathway regulating autophagy involving the Pat1-Lsm (Lsm1 to Lsm7) mRNA-binding complex. Under nitrogen-starvation conditions, Pat1-Lsm binds a specific subset of autophagy-related (ATG) transcripts and prevents their 3' to 5' degradation by the exosome complex, leading to ATG mRNA stabilization and accumulation. This process is regulated through Pat1 dephosphorylation, is necessary for the efficient expression of specific Atg proteins, and is required for robust autophagy induction during nitrogen starvation...
December 5, 2018: Molecular Cell
Xin Jin, Donglin Ding, Yuqian Yan, Hui Li, Bo Wang, Linlin Ma, Zhenqing Ye, Tao Ma, Qiang Wu, Daniel N Rodrigues, Manish Kohli, Rafael Jimenez, Liguo Wang, David W Goodrich, Johann de Bono, Haidong Dong, Heshui Wu, Runzhi Zhu, Haojie Huang
Aberrant expression of programmed death ligand-1 (PD-L1) in tumor cells promotes cancer progression by suppressing cancer immunity. The retinoblastoma protein RB is a tumor suppressor known to regulate the cell cycle, DNA damage response, and differentiation. Here, we demonstrate that RB interacts with nuclear factor κB (NF-κB) protein p65 and that their interaction is primarily dependent on CDK4/6-mediated serine-249/threonine-252 (S249/T252) phosphorylation of RB. RNA-seq analysis shows a subset of NF-κB pathway genes including PD-L1 are selectively upregulated by RB knockdown or CDK4/6 inhibitor...
December 3, 2018: Molecular Cell
Saranna Fanning, Aftabul Haque, Thibaut Imberdis, Valeriya Baru, M Inmaculada Barrasa, Silke Nuber, Daniel Termine, Nagendran Ramalingam, Gary P H Ho, Tallie Noble, Jackson Sandoe, Yali Lou, Dirk Landgraf, Yelena Freyzon, Gregory Newby, Frank Soldner, Elizabeth Terry-Kantor, Tae-Eun Kim, Harald F Hofbauer, Michel Becuwe, Rudolf Jaenisch, David Pincus, Clary B Clish, Tobias C Walther, Robert V Farese, Supriya Srinivasan, Michael A Welte, Sepp D Kohlwein, Ulf Dettmer, Susan Lindquist, Dennis Selkoe
In Parkinson's disease (PD), α-synuclein (αS) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in αS or lipid/fatty acid homeostasis affect each other. Lipidomic profiling of human αS-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides. These findings were recapitulated in rodent and human neuronal models of αS dyshomeostasis (overexpression; patient-derived triplication or E46K mutation; E46K mice). Preventing lipid droplet formation or augmenting OA increased αS yeast toxicity; suppressing the OA-generating enzyme stearoyl-CoA-desaturase (SCD) was protective...
December 1, 2018: Molecular Cell
Ryan M Sheridan, Nova Fong, Angelo D'Alessandro, David L Bentley
In addition to phosphodiester bond formation, RNA polymerase II has an RNA endonuclease activity, stimulated by TFIIS, which rescues complexes that have arrested and backtracked. How TFIIS affects transcription under normal conditions is poorly understood. We identified backtracking sites in human cells using a dominant-negative TFIIS (TFIISDN ) that inhibits RNA cleavage and stabilizes backtracked complexes. Backtracking is most frequent within 2 kb of start sites, consistent with slow elongation early in transcription, and in 3' flanking regions where termination is enhanced by TFIISDN , suggesting that backtracked pol II is a favorable substrate for termination...
November 27, 2018: Molecular Cell
Ling Wang, Charlie Y Mo, Michael R Wasserman, Jakob T Rostøl, Luciano A Marraffini, Shixin Liu
Adaptive immune systems must accurately distinguish between self and non-self in order to defend against invading pathogens while avoiding autoimmunity. Type III CRISPR-Cas systems employ guide RNA to recognize complementary RNA targets, which triggers the degradation of both the invader's transcripts and their template DNA. These systems can broadly eliminate foreign targets with multiple mutations but circumvent damage to the host genome. To explore the molecular basis for these features, we use single-molecule fluorescence microscopy to study the interaction between a type III-A ribonucleoprotein complex and various RNA substrates...
November 27, 2018: Molecular Cell
Ning Jia, Charlie Y Mo, Chongyuan Wang, Edward T Eng, Luciano A Marraffini, Dinshaw J Patel
Type ΙΙΙ CRISPR-Cas systems provide robust immunity against foreign RNA and DNA by sequence-specific RNase and target RNA-activated sequence-nonspecific DNase and RNase activities. We report on cryo-EM structures of Thermococcus onnurineus CsmcrRNA binary, CsmcrRNA -target RNA and CsmcrRNA -target RNAanti-tag ternary complexes in the 3.1 Å range. The topological features of the crRNA 5'-repeat tag explains the 5'-ruler mechanism for defining target cleavage sites, with accessibility of positions -2 to -5 within the 5'-repeat serving as sensors for avoidance of autoimmunity...
November 27, 2018: Molecular Cell
Ze Cheng, Christopher Frederick Mugler, Abdurrahman Keskin, Stefanie Hodapp, Leon Yen-Lee Chan, Karsten Weis, Philipp Mertins, Aviv Regev, Marko Jovanovic, Gloria Ann Brar
Levels of the ribosome, the conserved molecular machine that mediates translation, are tightly linked to cellular growth rate. In humans, ribosomopathies are diseases associated with cell-type-specific pathologies and reduced ribosomal protein (RP) levels. Because gene expression defects resulting from ribosome deficiency have not yet been experimentally defined, we systematically probed mRNA, translation, and protein signatures that were either unlinked from or linked to cellular growth rate in RP-deficient yeast cells...
November 27, 2018: Molecular Cell
Hotaka Kobayashi, Keisuke Shoji, Kaori Kiyokawa, Lumi Negishi, Yukihide Tomari
MicroRNAs (miRNAs) are loaded into the Argonaute subfamily of proteins (AGO) to form an effector complex that silences target genes. Empty but not miRNA-loaded AGO is selectively degraded across species. However, the mechanism and biological significance of selective AGO degradation remain unclear. We discovered a RING-type E3 ubiquitin ligase we named Iruka (Iru), which selectively ubiquitinates the empty form of Drosophila Ago1 to trigger its degradation. Iru preferentially binds empty Ago1 and ubiquitinates Lys514 in the L2 linker, which is predicted to be inaccessible in the miRNA-loaded state...
November 27, 2018: Molecular Cell
Zhengkui Zhang, Jinjin Du, Shuai Wang, Li Shao, Ke Jin, Fang Li, Bajin Wei, Wei Ding, Peifen Fu, Hans van Dam, Aijun Wang, Jin Jin, Chen Ding, Bing Yang, Min Zheng, Xin-Hua Feng, Kun-Liang Guan, Long Zhang
The transcriptional regulators YAP and TAZ play important roles in development, physiology, and tumorigenesis and are negatively controlled by the Hippo pathway. It is yet unknown why the YAP/ TAZ proteins are frequently activated in human malignancies in which the Hippo pathway is still active. Here, by a gain-of-function cancer metastasis screen, we discovered OTUB2 as a cancer stemness and metastasis-promoting factor that deubiquitinates and activates YAP/TAZ. We found OTUB2 to be poly-SUMOylated on lysine 233, and this SUMOylation enables it to bind YAP/TAZ...
November 21, 2018: Molecular Cell
Frederick E Tan, Shashank Sathe, Emily C Wheeler, Julia K Nussbacher, Samson Peter, Gene W Yeo
LIN28 RNA binding proteins are dynamically expressed throughout mammalian development and during disease. However, it remains unclear how changes in LIN28 expression define patterns of post-transcriptional gene regulation. Here we show that LIN28 expression level is a key variable that sets the magnitude of protein translation. By systematically varying LIN28B protein levels in human cells, we discovered a dose-dependent divergence in transcriptome-wide ribosome occupancy that enabled the formation of two discrete translational subpopulations composed of nearly all expressed genes...
November 19, 2018: Molecular Cell
Riko Hatakeyama, Marie-Pierre Péli-Gulli, Zehan Hu, Malika Jaquenoud, Guillermo Miguel Garcia Osuna, Alessandro Sardu, Jörn Dengjel, Claudio De Virgilio
The eukaryotic TORC1 kinase is a homeostatic controller of growth that integrates nutritional cues and mediates signals primarily from the surface of lysosomes or vacuoles. Amino acids activate TORC1 via the Rag GTPases that combine into structurally conserved multi-protein complexes such as the EGO complex (EGOC) in yeast. Here we show that Ego1, which mediates membrane-anchoring of EGOC via lipid modifications that it acquires while traveling through the trans-Golgi network, is separately sorted to vacuoles and perivacuolar endosomes...
November 19, 2018: Molecular Cell
Xiannian Zhang, Tianqi Li, Feng Liu, Yaqi Chen, Jiacheng Yao, Zeyao Li, Yanyi Huang, Jianbin Wang
Since its establishment in 2009, single-cell RNA sequencing (RNA-seq) has been a major driver behind progress in biomedical research. In developmental biology and stem cell studies, the ability to profile single cells confers particular benefits. Although most studies still focus on individual tissues or organs, the recent development of ultra-high-throughput single-cell RNA-seq has demonstrated potential power in characterizing more complex systems or even the entire body. However, although multiple ultra-high-throughput single-cell RNA-seq systems have attracted attention, no systematic comparison of these systems has been performed...
November 16, 2018: Molecular Cell
Yingying Pu, Yingxing Li, Xin Jin, Tian Tian, Qi Ma, Ziyi Zhao, Ssu-Yuan Lin, Zhanghua Chen, Binghui Li, Guang Yao, Mark C Leake, Chien-Jung Lo, Fan Bai
Cell dormancy is a widespread mechanism used by bacteria to evade environmental threats, including antibiotics. Here we monitored bacterial antibiotic tolerance and regrowth at the single-cell level and found that each individual survival cell shows different "dormancy depth," which in return regulates the lag time for cell resuscitation after removal of antibiotic. We further established that protein aggresome-a collection of endogenous protein aggregates-is an important indicator of bacterial dormancy depth, whose formation is promoted by decreased cellular ATP level...
November 16, 2018: Molecular Cell
Christian Dienemann, Björn Schwalb, Sandra Schilbach, Patrick Cramer
Transcription initiation requires opening of promoter DNA in the RNA polymerase II (Pol II) pre-initiation complex (PIC), but it remains unclear how this is achieved. Here we report the cryo-electron microscopic (cryo-EM) structure of a yeast PIC that contains underwound, distorted promoter DNA in the closed Pol II cleft. The DNA duplex axis is offset at the upstream edge of the initially melted DNA region (IMR) where DNA opening begins. Unstable IMRs are found in a subset of yeast promoters that we show can still initiate transcription after depletion of the transcription factor (TF) IIH (TFIIH) translocase Ssl2 (XPB in human) from the nucleus in vivo...
November 16, 2018: Molecular Cell
Valentina Aria, Joseph T P Yeeles
DNA replication commences at eukaryotic replication origins following assembly and activation of bidirectional CMG helicases. Once activated, CMG unwinds the parental DNA duplex and DNA polymerase α-primase initiates synthesis on both template strands. By utilizing an origin-dependent replication system using purified yeast proteins, we have mapped start sites for leading-strand replication. Synthesis is mostly initiated outside the origin sequence. Strikingly, rightward leading strands are primed left of the origin and vice versa...
November 16, 2018: Molecular Cell
Yaoyao Zhang, Zhiqiang Yan, Qingyuan Qin, Vicki Nisenblat, Hsun-Ming Chang, Yang Yu, Tianren Wang, Cuiling Lu, Ming Yang, Shuo Yang, Ying Yao, Xiaohui Zhu, Xi Xia, Yujiao Dang, Yixin Ren, Peng Yuan, Rong Li, Ping Liu, Hongyan Guo, Jinsong Han, Haojie He, Kun Zhang, Yiting Wang, Yu Wu, Meng Li, Jie Qiao, Jie Yan, Liying Yan
The dynamic transcriptional regulation and interactions of human germlines and surrounding somatic cells during folliculogenesis remain unknown. Using RNA sequencing (RNA-seq) analysis of human oocytes and corresponding granulosa cells (GCs) spanning five follicular stages, we revealed unique features in transcriptional machinery, transcription factor networks, and reciprocal interactions in human oocytes and GCs that displayed developmental-stage-specific expression patterns. Notably, we identified specific gene signatures of two cell types in particular developmental stage that may reflect developmental competency and ovarian reserve...
November 15, 2018: Molecular Cell
Fei Sun, Constantinos Chronis, Michael Kronenberg, Xiao-Fen Chen, Trent Su, Fides D Lay, Kathrin Plath, Siavash K Kurdistani, Michael F Carey
Metazoan chromosomes are sequentially partitioned into topologically associating domains (TADs) and then into smaller sub-domains. One class of sub-domains, insulated neighborhoods, are proposed to spatially sequester and insulate the enclosed genes through self-association and chromatin looping. However, it has not been determined functionally whether promoter-enhancer interactions and gene regulation are broadly restricted to within these loops. Here, we employed published datasets from murine embryonic stem cells (mESCs) to identify insulated neighborhoods that confine promoter-enhancer interactions and demarcate gene regulatory regions...
November 14, 2018: Molecular Cell
Timothy H Chang, Eugenio Mattei, Ildar Gainetdinov, Cansu Colpan, Zhiping Weng, Phillip D Zamore
In Drosophila, 23-30 nt long PIWI-interacting RNAs (piRNAs) direct the protein Piwi to silence germline transposon transcription. Most germline piRNAs derive from dual-strand piRNA clusters, heterochromatic transposon graveyards that are transcribed from both genomic strands. These piRNA sources are marked by the heterochromatin protein 1 homolog Rhino (Rhi), which facilitates their promoter-independent transcription, suppresses splicing, and inhibits transcriptional termination. Here, we report that the protein Maelstrom (Mael) represses canonical, promoter-dependent transcription in dual-strand clusters, allowing Rhi to initiate piRNA precursor transcription...
November 12, 2018: Molecular Cell
Emma J Chory, Joseph P Calarco, Nathaniel A Hathaway, Oliver Bell, Dana S Neel, Gerald R Crabtree
Recent studies have indicated that nucleosome turnover is rapid, occurring several times per cell cycle. To access the effect of nucleosome turnover on the epigenetic landscape, we investigated H3K79 methylation, which is produced by a single methyltransferase (Dot1l) with no known demethylase. Using chemical-induced proximity (CIP), we find that the valency of H3K79 methylation (mono-, di-, and tri-) is determined by nucleosome turnover rates. Furthermore, propagation of this mark is predicted by nucleosome turnover simulations over the genome and accounts for the asymmetric distribution of H3K79me toward the transcriptional unit...
November 9, 2018: Molecular Cell
Rocky Cheung, Kimberly D Insigne, David Yao, Christina P Burghard, Jeffrey Wang, Yun-Hua E Hsiao, Eric M Jones, Daniel B Goodman, Xinshu Xiao, Sriram Kosuri
Mutations that lead to splicing defects can have severe consequences on gene function and cause disease. Here, we explore how human genetic variation affects exon recognition by developing a multiplexed functional assay of splicing using Sort-seq (MFASS). We assayed 27,733 variants in the Exome Aggregation Consortium (ExAC) within or adjacent to 2,198 human exons in the MFASS minigene reporter and found that 3.8% (1,050) of variants, most of which are extremely rare, led to large-effect splice-disrupting variants (SDVs)...
November 8, 2018: Molecular Cell
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