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  • Identification of a localized nonsense-mediated decay pathway at the endoplasmic reticulum
    Genes Dev. (IF 9.527) Pub Date : 2020-07-02
    Dasa Longman; Kathryn A. Jackson-Jones; Magdalena M. Maslon; Laura C. Murphy; Robert S. Young; Jack J. Stoddart; Nele Hug; Martin S. Taylor; Dimitrios K. Papadopoulos; Javier F. Cáceres

    Nonsense-mediated decay (NMD) is a translation-dependent RNA quality control mechanism that occurs in the cytoplasm. However, it is unknown how NMD regulates the stability of RNAs translated at the endoplasmic reticulum (ER). Here, we identify a localized NMD pathway dedicated to ER-translated mRNAs. We previously identified NBAS, a component of the Syntaxin 18 complex involved in Golgi-to-ER trafficking

    更新日期:2020-07-02
  • A role for alternative splicing in circadian control of exocytosis and glucose homeostasis
    Genes Dev. (IF 9.527) Pub Date : 2020-07-02
    Biliana Marcheva; Mark Perelis; Benjamin J. Weidemann; Akihiko Taguchi; Haopeng Lin; Chiaki Omura; Yumiko Kobayashi; Marsha V. Newman; Eugene J. Wyatt; Elizabeth M. McNally; Jocelyn E. Manning Fox; Heekyung Hong; Archana Shankar; Emily C. Wheeler; Kathryn Moynihan Ramsey; Patrick E. MacDonald; Gene W. Yeo; Joseph Bass

    The circadian clock is encoded by a negative transcriptional feedback loop that coordinates physiology and behavior through molecular programs that remain incompletely understood. Here, we reveal rhythmic genome-wide alternative splicing (AS) of pre-mRNAs encoding regulators of peptidergic secretion within pancreatic β cells that are perturbed in Clock−/− and Bmal1−/− β-cell lines. We show that the

    更新日期:2020-07-02
  • Competition between maturation and degradation drives human snRNA 3' end quality control.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Rea M Lardelli,Jens Lykke-Andersen

    Polymerases and exonucleases act on 3′ ends of nascent RNAs to promote their maturation or degradation but how the balance between these activities is controlled to dictate the fates of cellular RNAs remains poorly understood. Here, we identify a central role for the human DEDD deadenylase TOE1 in distinguishing the fates of small nuclear (sn)RNAs of the spliceosome from unstable genome-encoded snRNA

    更新日期:2020-07-01
  • HDAC3 ensures stepwise epidermal stratification via NCoR/SMRT-reliant mechanisms independent of its histone deacetylase activity.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Katherine M Szigety,Fang Liu,Chase Y Yuan,Deborah J Moran,Jeremy Horrell,Heather R Gochnauer,Ronald N Cohen,Jonathan P Katz,Klaus H Kaestner,John T Seykora,John W Tobias,Mitchell A Lazar,Mingang Xu,Sarah E Millar

    Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. The class I HDAC, HDAC3, is of particular interest because it plays divergent roles in different tissues by partnering with tissue-specific transcription factors. We found that HDAC3 is expressed broadly in embryonic epidermis and is required for its orderly

    更新日期:2020-07-01
  • Twist-dependent ratchet functioning downstream from Dorsal revealed using a light-inducible degron.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Jihyun Irizarry,James McGehee,Goheun Kim,David Stein,Angelike Stathopoulos

    Graded transcription factors are pivotal regulators of embryonic patterning, but whether their role changes over time is unclear. A light-regulated protein degradation system was used to assay temporal dependence of the transcription factor Dorsal in dorsal–ventral axis patterning of Drosophila embryos. Surprisingly, the high-threshold target gene snail only requires Dorsal input early but not late

    更新日期:2020-07-01
  • Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Peng Gao,Changya Chen,Elizabeth D Howell,Yan Li,Joanna Tober,Yasin Uzun,Bing He,Long Gao,Qin Zhu,Arndt F Siekmann,Nancy A Speck,Kai Tan

    Hematopoietic stem cell (HSC) ontogeny is accompanied by dynamic changes in gene regulatory networks. We performed RNA-seq and histone mark ChIP-seq to define the transcriptomes and epigenomes of cells representing key developmental stages of HSC ontogeny in mice. The five populations analyzed were embryonic day 10.5 (E10.5) endothelium and hemogenic endothelium from the major arteries, an enriched

    更新日期:2020-07-01
  • A central role for canonical PRC1 in shaping the 3D nuclear landscape.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Shelagh Boyle,Ilya M Flyamer,Iain Williamson,Dipta Sengupta,Wendy A Bickmore,Robert S Illingworth

    Polycomb group (PcG) proteins silence gene expression by chemically and physically modifying chromatin. A subset of PcG target loci are compacted and cluster in the nucleus; a conformation that is thought to contribute to gene silencing. However, how these interactions influence gross nuclear organization and their relationship with transcription remains poorly understood. Here we examine the role

    更新日期:2020-07-01
  • Dynamic regulation of histone modifications and long-range chromosomal interactions during postmitotic transcriptional reactivation.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Hyeseon Kang,Maxim N Shokhirev,Zhichao Xu,Sahaana Chandran,Jesse R Dixon,Martin W Hetzer

    During mitosis, transcription of genomic DNA is dramatically reduced, before it is reactivated during nuclear reformation in anaphase/telophase. Many aspects of the underlying principles that mediate transcriptional memory and reactivation in the daughter cells remain unclear. Here, we used ChIP-seq on synchronized cells at different stages after mitosis to generate genome-wide maps of histone modifications

    更新日期:2020-07-01
  • UAP56/DDX39B is a major cotranscriptional RNA-DNA helicase that unwinds harmful R loops genome-wide.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Carmen Pérez-Calero,Aleix Bayona-Feliu,Xiaoyu Xue,Sonia I Barroso,Sergio Muñoz,Víctor M González-Basallote,Patrick Sung,Andrés Aguilera

    Nonscheduled R loops represent a major source of DNA damage and replication stress. Cells have different ways to prevent R-loop accumulation. One mechanism relies on the conserved THO complex in association with cotranscriptional RNA processing factors including the RNA-dependent ATPase UAP56/DDX39B and histone modifiers such as the SIN3 deacetylase in humans. We investigated the function of UAP56/DDX39B

    更新日期:2020-07-01
  • Nutrient-dependent control of RNA polymerase II elongation rate regulates specific gene expression programs by alternative polyadenylation.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Carlo Yague-Sanz,Yann Vanrobaeys,Ronan Fernandez,Maxime Duval,Marc Larochelle,Jude Beaudoin,Julien Berro,Simon Labbé,Pierre-Étienne Jacques,François Bachand

    Transcription by RNA polymerase II (RNAPII) is a dynamic process with frequent variations in the elongation rate. However, the physiological relevance of variations in RNAPII elongation kinetics has remained unclear. Here we show in yeast that a RNAPII mutant that reduces the transcription elongation rate causes widespread changes in alternative polyadenylation (APA). We unveil two mechanisms by which

    更新日期:2020-07-01
  • RNA polymerase III transcription as a disease factor
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Meghdad Yeganeh; Nouria Hernandez

    RNA polymerase (Pol) III is responsible for transcription of different noncoding genes in eukaryotic cells, whose RNA products have well-defined functions in translation and other biological processes for some, and functions that remain to be defined for others. For all of them, however, new functions are being described. For example, Pol III products have been reported to regulate certain proteins

    更新日期:2020-07-01
  • A genome-wide and cotranscriptional suppressor of R loops
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Jacob P. Matson; Lee Zou

    R loops arise from hybridization of RNA transcripts with template DNA during transcription. Unrepaired R loops lead to transcription–replication collisions, causing DNA damage and genomic instability. In this issue of Genes & Development, Pérez-Calero and colleagues (pp. 898–912) identify UAP56 as a cotranscriptional RNA–DNA helicase that unwinds R loops. They found that UAP56 helicase activity is

    更新日期:2020-07-01
  • Collapse of the hepatic gene regulatory network in the absence of FoxA factors.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-19
    Yitzhak Reizel,Ashleigh Morgan,Long Gao,Yemin Lan,Elisabetta Manduchi,Eric L Waite,Amber W Wang,Andrew Wells,Klaus H Kaestner

    The FoxA transcription factors are critical for liver development through their pioneering activity, which initiates a highly complex regulatory network thought to become progressively resistant to the loss of any individual hepatic transcription factor via mutual redundancy. To investigate the dispensability of FoxA factors for maintaining this regulatory network, we ablated all FoxA genes in the

    更新日期:2020-06-19
  • Human RTEL1 associates with Poldip3 to facilitate responses to replication stress and R-loop resolution.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-19
    Andrea Björkman,Søren L Johansen,Lin Lin,Mike Schertzer,Dimitris C Kanellis,Anna-Maria Katsori,Søren T Christensen,Yonglun Luo,Jens S Andersen,Simon J Elsässer,Arturo Londono-Vallejo,Jiri Bartek,Kenneth B Schou

    RTEL1 helicase is a component of DNA repair and telomere maintenance machineries. While RTEL1's role in DNA replication is emerging, how RTEL1 preserves genomic stability during replication remains elusive. Here we used a range of proteomic, biochemical, cell, and molecular biology and gene editing approaches to provide further insights into potential role(s) of RTEL1 in DNA replication and genome

    更新日期:2020-06-19
  • Corrigendum: Developmental regulation of cell type-specific transcription by novel promoter-proximal sequence elements.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Dan Lu,Ho-Su Sin,Chenggang Lu,Margaret T Fuller

    Genes & Development 34: 663–677 (2020)

    更新日期:2020-06-01
  • Progress toward understanding chromosome silencing by Xist RNA.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Neil Brockdorff,Joseph S Bowness,Guifeng Wei

    The X inactive-specific transcript (Xist) gene is the master regulator of X chromosome inactivation in mammals. Xist produces a long noncoding (lnc)RNA that accumulates over the entire length of the chromosome from which it is transcribed, recruiting factors to modify underlying chromatin and silence X-linked genes in cis. Recent years have seen significant progress in identifying important functional

    更新日期:2020-06-01
  • After the break: DSB end processing in mouse meiosis.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Kevin Brick,Florencia Pratto,R Daniel Camerini-Otero

    The exchange of genetic information between parental chromosomes in meiosis is an integral process for the creation of gametes. To generate a crossover, hundreds of DNA double-strand breaks (DSBs) are introduced in the genome of each meiotic cell by the SPO11 protein. The nucleolytic resection of DSB-adjacent DNA is a key step in meiotic DSB repair, but this process has remained understudied. In this

    更新日期:2020-06-01
  • Transcriptional down-regulation of metabolic genes by Gdown1 ablation induces quiescent cell re-entry into the cell cycle.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Miki Jishage,Keiichi Ito,Chi-Shuen Chu,Xiaoling Wang,Masashi Yamaji,Robert G Roeder

    Liver regeneration and metabolism are highly interconnected. Here, we show that hepatocyte-specific ablation of RNA polymerase II (Pol II)-associated Gdown1 leads to down-regulation of highly expressed genes involved in plasma protein synthesis and metabolism, a concomitant cell cycle re-entry associated with induction of cell cycle-related genes (including cyclin D1), and up-regulation of p21 through

    更新日期:2020-06-01
  • ALS/FTD-associated protein FUS induces mitochondrial dysfunction by preferentially sequestering respiratory chain complex mRNAs.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Yueh-Lin Tsai,Tristan H Coady,Lei Lu,Dinghai Zheng,Isabel Alland,Bin Tian,Neil A Shneider,James L Manley

    Dysregulation of the DNA/RNA-binding protein FUS causes certain subtypes of ALS/FTD by largely unknown mechanisms. Recent evidence has shown that FUS toxic gain of function due either to mutations or to increased expression can disrupt critical cellular processes, including mitochondrial functions. Here, we demonstrate that in human cells overexpressing wild-type FUS or expressing mutant derivatives

    更新日期:2020-06-01
  • TEX15 associates with MILI and silences transposable elements in male germ cells.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Fang Yang,Yemin Lan,Radha Raman Pandey,David Homolka,Shelley L Berger,Ramesh S Pillai,Marisa S Bartolomei,P Jeremy Wang

    DNA methylation is a major silencing mechanism of transposable elements (TEs). Here we report that TEX15, a testis-specific protein, is required for TE silencing. TEX15 is expressed in embryonic germ cells and functions during genome-wide epigenetic reprogramming. The Tex15 mutant exhibits DNA hypomethylation in TEs at a level similar to Mili and Dnmt3c but not Miwi2 mutants. TEX15 is associated with

    更新日期:2020-06-01
  • 4E-T-bound mRNAs are stored in a silenced and deadenylated form.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Felix Räsch,Ramona Weber,Elisa Izaurralde,Cátia Igreja

    Human 4E-T is an eIF4E-binding protein (4E-BP) present in processing (P)-bodies that represses translation and regulates decay of mRNAs destabilized by AU-rich elements and microRNAs (miRNAs). However, the underlying regulatory mechanisms are still unclear. Here, we show that upon mRNA binding 4E-T represses translation and promotes deadenylation via the recruitment of the CCR4–NOT deadenylase complex

    更新日期:2020-06-01
  • Distinct roles of BRCA2 in replication fork protection in response to hydroxyurea and DNA interstrand cross-links.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Kimberly A Rickman,Raymond J Noonan,Francis P Lach,Sunandini Sridhar,Anderson T Wang,Avinash Abhyankar,Athena Huang,Michael Kelly,Arleen D Auerbach,Agata Smogorzewska

    DNA interstrand cross-links (ICLs) are a form of DNA damage that requires the interplay of a number of repair proteins including those of the Fanconi anemia (FA) and the homologous recombination (HR) pathways. Pathogenic variants in the essential gene BRCA2/FANCD1, when monoallelic, predispose to breast and ovarian cancer, and when biallelic, result in a severe subtype of Fanconi anemia. BRCA2 function

    更新日期:2020-06-01
  • Molecular structures and mechanisms of DNA break processing in mouse meiosis.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Shintaro Yamada,Anjali Gupta Hinch,Hisashi Kamido,Yongwei Zhang,Winfried Edelmann,Scott Keeney

    Exonucleolytic resection, critical to repair double-strand breaks (DSBs) by recombination, is not well understood, particularly in mammalian meiosis. Here, we define structures of resected DSBs in mouse spermatocytes genome-wide at nucleotide resolution. Resection tracts averaged 1100 nt, but with substantial fine-scale heterogeneity at individual hot spots. Surprisingly, EXO1 is not the major 5′ →

    更新日期:2020-06-01
  • The spatial regulation of condensin activity in chromosome condensation.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Rebecca Lamothe,Lorenzo Costantino,Douglas E Koshland

    Condensin mediates chromosome condensation, which is essential for proper chromosome segregation during mitosis. Prior to anaphase of budding yeast, the ribosomal DNA (RDN) condenses to a thin loop that is distinct from the rest of the chromosomes. We provide evidence that the establishment and maintenance of this RDN condensation requires the regulation of condensin by Cdc5p (polo) kinase. We show

    更新日期:2020-06-01
  • REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Shuxi Qiao,Siang-Boon Koh,Varunika Vivekanandan,Devika Salunke,Krushna Chandra Patra,Elma Zaganjor,Kenneth Ross,Yusuke Mizukami,Sarah Jeanfavre,Athena Chen,Mari Mino-Kenudson,Sridhar Ramaswamy,Clary Clish,Marcia Haigis,Nabeel Bardeesy,Leif W Ellisen

    Human cancers with activating RAS mutations are typically highly aggressive and treatment-refractory, yet RAS mutation itself is insufficient for tumorigenesis, due in part to profound metabolic stress induced by RAS activation. Here we show that loss of REDD1, a stress-induced metabolic regulator, is sufficient to reprogram lipid metabolism and drive progression of RAS mutant cancers. Redd1 deletion

    更新日期:2020-06-01
  • Getting started: altering promoter choice as a mechanism for cell type differentiation.
    Genes Dev. (IF 9.527) Pub Date : 2020-05-01
    Mukulika Ray,Erica Larschan

    In this issue of Genes & Development, Lu and colleagues (pp. 663-677) have discovered a key new mechanism of alternative promoter choice that is involved in differentiation of spermatocytes. Promoter choice has strong potential as mechanism for differentiation of many different cell types.

    更新日期:2020-05-01
  • Targeted chemotherapy overcomes drug resistance in melanoma.
    Genes Dev. (IF 9.527) Pub Date : 2020-04-02
    Jingyin Yue,Roberto Vendramin,Fan Liu,Omar Lopez,Monica G Valencia,Helena Gomes Dos Santos,Gabriel Gaidosh,Felipe Beckedorff,Ezra Blumenthal,Lucia Speroni,Stephen D Nimer,Jean-Christophe Marine,Ramin Shiekhattar

    The emergence of drug resistance is a major obstacle for the success of targeted therapy in melanoma. Additionally, conventional chemotherapy has not been effective as drug-resistant cells escape lethal DNA damage effects by inducing growth arrest commonly referred to as cellular dormancy. We present a therapeutic strategy termed "targeted chemotherapy" by depleting protein phosphatase 2A (PP2A) or

    更新日期:2020-05-01
  • Positive autofeedback regulation of Ptf1a transcription generates the levels of PTF1A required to generate itch circuit neurons.
    Genes Dev. (IF 9.527) Pub Date : 2020-04-02
    Bishakha Mona,Juan Villarreal,Trisha K Savage,Rahul K Kollipara,Brooke E Boisvert,Jane E Johnson

    Peripheral somatosensory input is modulated in the dorsal spinal cord by a network of excitatory and inhibitory interneurons. PTF1A is a transcription factor essential in dorsal neural tube progenitors for specification of these inhibitory neurons. Thus, mechanisms regulating Ptf1a expression are key for generating neuronal circuits underlying somatosensory behaviors. Mutations targeted to distinct

    更新日期:2020-05-01
  • Embryo integrity regulates maternal proteostasis and stress resilience.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-26
    Ambre J Sala,Laura C Bott,Renee M Brielmann,Richard I Morimoto

    The proteostasis network is regulated by transcellular communication to promote health and fitness in metazoans. In Caenorhabditis elegans, signals from the germline initiate the decline of proteostasis and repression of cell stress responses at reproductive maturity, indicating that commitment to reproduction is detrimental to somatic health. Here we show that proteostasis and stress resilience are

    更新日期:2020-05-01
  • Telomere length heterogeneity in ALT cells is maintained by PML-dependent localization of the BTR complex to telomeres.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-26
    Taylor K Loe,Julia Su Zhou Li,Yuxiang Zhang,Benura Azeroglu,Michael Nicholas Boddy,Eros Lazzerini Denchi

    Telomeres consist of TTAGGG repeats bound by protein complexes that serve to protect the natural end of linear chromosomes. Most cells maintain telomere repeat lengths by using the enzyme telomerase, although there are some cancer cells that use a telomerase-independent mechanism of telomere extension, termed alternative lengthening of telomeres (ALT). Cells that use ALT are characterized, in part

    更新日期:2020-05-01
  • The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-26
    Valentina V Ignatova,Paul Stolz,Steffen Kaiser,Tobias H Gustafsson,Palma Rico Lastres,Adrián Sanz-Moreno,Yi-Li Cho,Oana V Amarie,Antonio Aguilar-Pimentel,Tanja Klein-Rodewald,Julia Calzada-Wack,Lore Becker,Susan Marschall,Markus Kraiger,Lillian Garrett,Claudia Seisenberger,Sabine M Hölter,Kayla Borland,Erik Van De Logt,Pascal W T C Jansen,Marijke P Baltissen,Magdalena Valenta,Michiel Vermeulen,Wolfgang

    Covalent chemical modifications of cellular RNAs directly impact all biological processes. However, our mechanistic understanding of the enzymes catalyzing these modifications, their substrates and biological functions, remains vague. Amongst RNA modifications N6-methyladenosine (m6A) is widespread and found in messenger (mRNA), ribosomal (rRNA), and noncoding RNAs. Here, we undertook a systematic

    更新日期:2020-05-01
  • Developmental regulation of cell type-specific transcription by novel promoter-proximal sequence elements.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-26
    Dan Lu,Ho-Su Sin,Chenggang Lu,Margaret T Fuller

    Cell type-specific transcriptional programs that drive differentiation of specialized cell types are key players in development and tissue regeneration. One of the most dramatic changes in the transcription program in Drosophila occurs with the transition from proliferating spermatogonia to differentiating spermatocytes, with >3000 genes either newly expressed or expressed from new alternative promoters

    更新日期:2020-05-01
  • Autophagy promotes mammalian survival by suppressing oxidative stress and p53.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-19
    Yang Yang,Gizem Karsli-Uzunbas,Laura Poillet-Perez,Akshada Sawant,Zhixian Sherrie Hu,Yuhan Zhao,Dirk Moore,Wenwei Hu,Eileen White

    Autophagy captures intracellular components and delivers them to lysosomes for degradation and recycling. Conditional autophagy deficiency in adult mice causes liver damage, shortens life span to 3 mo due to neurodegeneration, and is lethal upon fasting. As autophagy deficiency causes p53 induction and cell death in neurons, we sought to test whether p53 mediates the lethal consequences of autophagy

    更新日期:2020-05-01
  • Drosophila estrogen-related receptor directs a transcriptional switch that supports adult glycolysis and lipogenesis.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-12
    Katherine Beebe,Marcy M Robins,Edgar J Hernandez,Geanette Lam,Michael A Horner,Carl S Thummel

    Metabolism and development must be closely coupled to meet the changing physiological needs of each stage in the life cycle. The molecular mechanisms that link these pathways, however, remain poorly understood. Here we show that the Drosophila estrogen-related receptor (dERR) directs a transcriptional switch in mid-pupae that promotes glucose oxidation and lipogenesis in young adults. dERR mutant adults

    更新日期:2020-05-01
  • Blunting senescence boosts liver regeneration
    Genes Dev. (IF 9.527) Pub Date : 2020-04-01
    Jodie Birch; Jesus Gil

    The mammalian liver possesses a unique capacity for regeneration. However, this regenerative potential declines with age due to unknown mechanisms. In this issue of Genes & Development, Ritschka and colleagues (pp. 489–494). compare liver regeneration upon partial hepatectomy in young and adult mice. Partial hepatectomy causes a transient increase in p21 in a subpopulation of hepatocytes that persists

    更新日期:2020-04-01
  • Structure and mechanism of the RNA polymerase II transcription machinery
    Genes Dev. (IF 9.527) Pub Date : 2020-04-01
    Allison C. Schier; Dylan J. Taatjes

    RNA polymerase II (Pol II) transcribes all protein-coding genes and many noncoding RNAs in eukaryotic genomes. Although Pol II is a complex, 12-subunit enzyme, it lacks the ability to initiate transcription and cannot consistently transcribe through long DNA sequences. To execute these essential functions, an array of proteins and protein complexes interact with Pol II to regulate its activity. In

    更新日期:2020-04-01
  • The senotherapeutic drug ABT-737 disrupts aberrant p21 expression to restore liver regeneration in adult mice
    Genes Dev. (IF 9.527) Pub Date : 2020-04-01
    Birgit Ritschka; Tania Knauer-Meyer; Daniel Sampaio Gonçalves; Alba Mas; Jean-Luc Plassat; Matej Durik; Hugues Jacobs; Elisa Pedone; Umberto Di Vicino; Maria Pia Cosma; William M. Keyes

    Young mammals possess a limited regenerative capacity in some tissues, which is lost upon maturation. We investigated whether cellular senescence might play a role in such loss during liver regeneration. We found that following partial hepatectomy, the senescence-associated genes p21, p16Ink4a, and p19Arf become dynamically expressed in different cell types when regenerative capacity decreases, but

    更新日期:2020-04-01
  • The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation
    Genes Dev. (IF 9.527) Pub Date : 2020-04-01
    Rabih El-Merahbi; Jonathan Trujillo Viera; Angel Loza Valdes; Katarzyna Kolczynska; Saskia Reuter; Mona C. Löffler; Manuela Erk; Carsten P. Ade; Till Karwen; Alexander E. Mayer; Martin Eilers; Grzegorz Sumara

    Obesity-induced diabetes affects >400 million people worldwide. Uncontrolled lipolysis (free fatty acid release from adipocytes) can contribute to diabetes and obesity. To identify future therapeutic avenues targeting this pathway, we performed a high-throughput screen and identified the extracellular-regulated kinase 3 (ERK3) as a hit. We demonstrated that β-adrenergic stimulation stabilizes ERK3

    更新日期:2020-04-01
  • Loss of an H3K9me anchor rescues laminopathy-linked changes in nuclear organization and muscle function in an Emery-Dreifuss muscular dystrophy model
    Genes Dev. (IF 9.527) Pub Date : 2020-04-01
    Jennifer C. Harr; Christoph D. Schmid; Celia Muñoz-Jiménez; Raquel Romero-Bueno; Véronique Kalck; Adriana Gonzalez-Sandoval; Michael H. Hauer; Jan Padeken; Peter Askjaer; Anna Mattout; Susan M. Gasser

    Mutations in the nuclear structural protein lamin A produce rare, tissue-specific diseases called laminopathies. The introduction of a human Emery-Dreifuss muscular dystrophy (EDMD)-inducing mutation into the C. elegans lamin (LMN-Y59C), recapitulates many muscular dystrophy phenotypes, and correlates with hyper-sequestration of a heterochromatic array at the nuclear periphery in muscle cells. Using

    更新日期:2020-04-01
  • Cerebral organoid and mouse models reveal a RAB39b-PI3K-mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes.
    Genes Dev. (IF 9.527) Pub Date : 2020-04-01
    Wei Zhang,Li Ma,Mei Yang,Qiang Shao,Jian Xu,Zhipeng Lu,Zhen Zhao,Rong Chen,Yang Chai,Jian-Fu Chen

    Dysregulation of early neurodevelopment is implicated in macrocephaly/autism disorders. However, the mechanism underlying this dysregulation, particularly in human cells, remains poorly understood. Mutations in the small GTPase gene RAB39b are associated with X-linked macrocephaly, autism spectrum disorder (ASD), and intellectual disability. The in vivo roles of RAB39b in the brain remain unknown.

    更新日期:2020-04-01
  • Coordination of germ layer lineage choice by TET1 during primed pluripotency.
    Genes Dev. (IF 9.527) Pub Date : 2020-04-01
    Xinlong Luo,Bernard K van der Veer,Lei Sun,Michela Bartoccetti,Matteo Boretto,Hugo Vankelecom,Rita Khoueiry,Kian Peng Koh

    Gastrulation in the early postimplantation stage mammalian embryo begins when epiblast cells ingress to form the primitive streak or develop as the embryonic ectoderm. The DNA dioxygenase Tet1 is highly expressed in the epiblast and yet continues to regulate lineage specification during gastrulation when its expression is diminished. Here, we show how Tet1 plays a pivotal role upstream of germ layer

    更新日期:2020-04-01
  • Critical roles of phosphoinositides and NF2 in Hippo pathway regulation.
    Genes Dev. (IF 9.527) Pub Date : 2020-04-01
    Audrey W Hong,Zhipeng Meng,Steven W Plouffe,Zhijie Lin,Mingjie Zhang,Kun-Liang Guan

    The Hippo pathway is a master regulator of tissue homeostasis and organ size. NF2 is a well-established tumor suppressor, and loss of NF2 severely compromises Hippo pathway activity. However, the precise mechanism of how NF2 mediates upstream signals to regulate the Hippo pathway is not clear. Here we report that, in mammalian cells, NF2's lipid-binding ability is critical for its function in activating

    更新日期:2020-04-01
  • Estrogen-related receptors are targetable ROS sensors.
    Genes Dev. (IF 9.527) Pub Date : 2020-04-01
    Mathieu Vernier,Catherine R Dufour,Shawn McGuirk,Charlotte Scholtes,Xiaojing Li,Guillaume Bourmeau,Hellen Kuasne,Morag Park,Julie St-Pierre,Etienne Audet-Walsh,Vincent Giguère

    Excessive reactive oxygen species (ROS) can cause oxidative stress and consequently cell injury contributing to a wide range of diseases. Addressing the critical gaps in our understanding of the adaptive molecular events downstream ROS provocation holds promise for the identification of druggable metabolic vulnerabilities. Here, we unveil a direct molecular link between the activity of two estrogen-related

    更新日期:2020-04-01
  • MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling.
    Genes Dev. (IF 9.527) Pub Date : 2020-04-01
    Divya Venkatesh,Nicholas A O'Brien,Fereshteh Zandkarimi,David R Tong,Michael E Stokes,Denise E Dunn,Everett S Kengmana,Allegra T Aron,Alyssa M Klein,Joleen M Csuka,Sung-Hwan Moon,Marcus Conrad,Christopher J Chang,Donald C Lo,Angelo D'Alessandro,Carol Prives,Brent R Stockwell

    MDM2 and MDMX, negative regulators of the tumor suppressor p53, can work separately and as a heteromeric complex to restrain p53's functions. MDM2 also has pro-oncogenic roles in cells, tissues, and animals that are independent of p53. There is less information available about p53-independent roles of MDMX or the MDM2-MDMX complex. We found that MDM2 and MDMX facilitate ferroptosis in cells with or

    更新日期:2020-04-01
  • Corrigendum: Control of noncoding RNA production and histone levels by a 5' tRNA fragment.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-01
    Ana Boskovic,Xin Yang Bing,Ebru Kaymak,Oliver J Rando

    Genes & Development 34: 118–131 (2020)

    更新日期:2020-03-02
  • Pioneering meiotic recombination.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-01
    Kris G Alavattam,Hironori Abe,Satoshi H Namekawa

    To induce cell type-specific forms of gene regulation, pioneer factors open tightly packed, inaccessible chromatin sites, enabling the molecular machinery to act on functionally significant information encoded in DNA. While previous studies of pioneer factors have revealed their functions in transcriptional regulation, pioneer factors that open chromatin for other physiological events remain undetermined

    更新日期:2020-03-01
  • Interplay between compartmentalized NAD+ synthesis and consumption: a focus on the PARP family.
    Genes Dev. (IF 9.527) Pub Date : 2020-02-06
    Michael S Cohen

    Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for redox enzymes, but also moonlights as a substrate for signaling enzymes. When used as a substrate by signaling enzymes, it is consumed, necessitating the recycling of NAD+ consumption products (i.e., nicotinamide) via a salvage pathway in order to maintain NAD+ homeostasis. A major family of NAD+ consumers in mammalian cells are

    更新日期:2020-02-06
  • The role of ADP-ribose metabolism in metabolic regulation, adipose tissue differentiation, and metabolism.
    Genes Dev. (IF 9.527) Pub Date : 2020-02-06
    Magdolna Szántó,Peter Bai

    Poly(ADP-ribose) polymerases (PARPs or ARTDs), originally described as DNA repair factors, have metabolic regulatory roles. PARP1, PARP2, PARP7, PARP10, and PARP14 regulate central and peripheral carbohydrate and lipid metabolism and often channel pathological disruptive metabolic signals. PARP1 and PARP2 are crucial for adipocyte differentiation, including the commitment toward white, brown, or beige

    更新日期:2020-02-06
  • PARP and PARG inhibitors in cancer treatment.
    Genes Dev. (IF 9.527) Pub Date : 2020-02-06
    Dea Slade

    Oxidative and replication stress underlie genomic instability of cancer cells. Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells. Precision medicine has revolutionized cancer therapy by putting forth the concept of selective targeting of cancer cells. Poly(ADP-ribose) polymerase (PARP) inhibitors represent a successful

    更新日期:2020-02-06
  • The impact of PARPs and ADP-ribosylation on inflammation and host-pathogen interactions.
    Genes Dev. (IF 9.527) Pub Date : 2020-02-06
    Anthony R Fehr,Sasha A Singh,Catherine M Kerr,Shin Mukai,Hideyuki Higashi,Masanori Aikawa

    Poly-adenosine diphosphate-ribose polymerases (PARPs) promote ADP-ribosylation, a highly conserved, fundamental posttranslational modification (PTM). PARP catalytic domains transfer the ADP-ribose moiety from NAD+ to amino acid residues of target proteins, leading to mono- or poly-ADP-ribosylation (MARylation or PARylation). This PTM regulates various key biological and pathological processes. In this

    更新日期:2020-02-06
  • Nuclear PARPs and genome integrity.
    Genes Dev. (IF 9.527) Pub Date : 2020-02-06
    Kameron Azarm,Susan Smith

    Effective maintenance and stability of our genomes is essential for normal cell division, tissue homeostasis, and cellular and organismal fitness. The processes of chromosome replication and segregation require continual surveillance to insure fidelity. Accurate and efficient repair of DNA damage preserves genome integrity, which if lost can lead to multiple diseases, including cancer. Poly(ADP-ribose)

    更新日期:2020-02-06
  • PARPs and ADP-ribosylation in RNA biology: from RNA expression and processing to protein translation and proteostasis.
    Genes Dev. (IF 9.527) Pub Date : 2020-02-06
    Dae-Seok Kim,Sridevi Challa,Aarin Jones,W Lee Kraus

    ADP-ribosylation (ADPRylation) is a posttranslational modification of proteins discovered nearly six decades ago, but many important questions remain regarding its molecular functions and biological roles, as well as the activity of the ADP-ribose (ADPR) transferase enzymes (PARP family members) that catalyze it. Growing evidence indicates that PARP-mediated ADPRylation events are key regulators of

    更新日期:2020-02-06
  • (ADP-ribosyl)hydrolases: structure, function, and biology.
    Genes Dev. (IF 9.527) Pub Date : 2020-02-06
    Johannes Gregor Matthias Rack,Luca Palazzo,Ivan Ahel

    ADP-ribosylation is an intricate and versatile posttranslational modification involved in the regulation of a vast variety of cellular processes in all kingdoms of life. Its complexity derives from the varied range of different chemical linkages, including to several amino acid side chains as well as nucleic acids termini and bases, it can adopt. In this review, we provide an overview of the different

    更新日期:2020-02-06
  • PARPs and ADP-ribosylation: 60 years on.
    Genes Dev. (IF 9.527) Pub Date : 2020-02-06
    W Lee Kraus

    Work on PARPs-a family of enzymes that catalyze ADP-ribosylation, a posttranslational modification of proteins-has resulted in major advances and reached important milestones. The past decade has seen new discoveries in areas well beyond the historical focus on DNA repair, which are having impacts on the understanding and treatment of human disease. This special focus section of Genes & Development

    更新日期:2020-02-06
  • Better safe than sorry-preventing mitotic segregation of meiotic chromosomes.
    Genes Dev. (IF 9.527) Pub Date : 2020-02-01
    Régis E Meyer,Dean S Dawson

    The distinctive segregation patterns of chromosomes in mitosis and meiosis are dictated in part by the kinetochores, the structures on chromosomes that attach them to the microtubules of the spindle. Inappropriate mitosis-like chromosome segregation in meiosis leads to gametes with incorrect chromosome numbers. New findings by Chen and colleagues (pp. 209-225) in this issue of Genes & Development reveal

    更新日期:2020-02-01
  • Noncoding SNPs influence a distinct phase of Polycomb silencing to destabilize long-term epigenetic memory at Arabidopsis FLC.
    Genes Dev. (IF 9.527) Pub Date : 2020-01-30
    Julia I Qüesta,Rea L Antoniou-Kourounioti,Stefanie Rosa,Peijin Li,Susan Duncan,Charles Whittaker,Martin Howard,Caroline Dean

    In Arabidopsis thaliana, the cold-induced epigenetic regulation of FLOWERING LOCUS C (FLC) involves distinct phases of Polycomb repressive complex 2 (PRC2) silencing. During cold, a PHD-PRC2 complex metastably and digitally nucleates H3K27me3 within FLC On return to warm, PHD-PRC2 spreads across the locus delivering H3K27me3 to maintain long-term silencing. Here, we studied natural variation in this

    更新日期:2020-01-30
  • Recurrent SRSF2 mutations in MDS affect both splicing and NMD.
    Genes Dev. (IF 9.527) Pub Date : 2020-01-30
    Mohammad Alinoor Rahman,Kuan-Ting Lin,Robert K Bradley,Omar Abdel-Wahab,Adrian R Krainer

    Oncogenic mutations in the RNA splicing factors SRSF2, SF3B1, and U2AF1 are the most frequent class of mutations in myelodysplastic syndromes and are also common in clonal hematopoiesis, acute myeloid leukemia, chronic lymphocytic leukemia, and a variety of solid tumors. They cause genome-wide splicing alterations that affect important regulators of hematopoiesis. Several mRNA isoforms promoted by

    更新日期:2020-01-30
  • HELLS and PRDM9 form a pioneer complex to open chromatin at meiotic recombination hot spots.
    Genes Dev. (IF 9.527) Pub Date : 2020-01-30
    Catrina Spruce,Sibongakonke Dlamini,Guruprasad Ananda,Naomi Bronkema,Hui Tian,Kenneth Paigen,Gregory W Carter,Christopher L Baker

    Chromatin barriers prevent spurious interactions between regulatory elements and DNA-binding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hot spots during meiosis. Here we show that the chromatin remodeler HELLS and DNA-binding protein PRDM9 function together to open chromatin at hot spots and provide access for the DNA double-strand break

    更新日期:2020-01-30
  • Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence.
    Genes Dev. (IF 9.527) Pub Date : 2020-01-30
    Maria Grazia Vizioli,Tianhui Liu,Karl N Miller,Neil A Robertson,Kathryn Gilroy,Anthony B Lagnado,Arantxa Perez-Garcia,Christos Kiourtis,Nirmalya Dasgupta,Xue Lei,Patrick J Kruger,Colin Nixon,William Clark,Diana Jurk,Thomas G Bird,João F Passos,Shelley L Berger,Zhixun Dou,Peter D Adams

    Cellular senescence is a potent tumor suppressor mechanism but also contributes to aging and aging-related diseases. Senescence is characterized by a stable cell cycle arrest and a complex proinflammatory secretome, termed the senescence-associated secretory phenotype (SASP). We recently discovered that cytoplasmic chromatin fragments (CCFs), extruded from the nucleus of senescent cells, trigger the

    更新日期:2020-01-30
  • Aurora B-dependent Ndc80 degradation regulates kinetochore composition in meiosis.
    Genes Dev. (IF 9.527) Pub Date : 2020-01-09
    Jingxun Chen,Andrew Liao,Emily N Powers,Hanna Liao,Lori A Kohlstaedt,Rena Evans,Ryan M Holly,Jenny Kim Kim,Marko Jovanovic,Elçin Ünal

    The kinetochore complex is a conserved machinery that connects chromosomes to spindle microtubules. During meiosis, the kinetochore is restructured to accommodate a specialized chromosome segregation pattern. In budding yeast, meiotic kinetochore remodeling is mediated by the temporal changes in the abundance of a single subunit called Ndc80. We previously described the regulatory events that control

    更新日期:2020-01-09
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