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  • Targeted chemotherapy overcomes drug resistance in melanoma
    Genes Dev. (IF 8.99) 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:2020-04-03
  • Positive autofeedback regulation of Ptf1a transcription generates the levels of PTF1A required to generate itch circuit neurons
    Genes Dev. (IF 8.99) 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:2020-04-03
  • Blunting senescence boosts liver regeneration
    Genes Dev. (IF 8.99) 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 8.99) 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 8.99) 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 8.99) 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
  • Critical roles of phosphoinositides and NF2 in Hippo pathway regulation.
    Genes Dev. (IF 8.99) 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
  • MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling.
    Genes Dev. (IF 8.99) 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
  • Estrogen-related receptors are targetable ROS sensors.
    Genes Dev. (IF 8.99) 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
  • 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 8.99) 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 8.99) 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 8.99) 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
  • The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs
    Genes Dev. (IF 8.99) 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;

    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:2020-03-30
  • Embryo integrity regulates maternal proteostasis and stress resilience
    Genes Dev. (IF 8.99) 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:2020-03-27
  • Telomere length heterogeneity in ALT cells is maintained by PML-dependent localization of the BTR complex to telomeres
    Genes Dev. (IF 8.99) 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:2020-03-27
  • Developmental regulation of cell type-specific transcription by novel promoter-proximal sequence elements
    Genes Dev. (IF 8.99) 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:2020-03-27
  • Drosophila estrogen-related receptor directs a transcriptional switch that supports adult glycolysis and lipogenesis.
    Genes Dev. (IF 8.99) 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:2020-03-12
  • Corrigendum: Control of noncoding RNA production and histone levels by a 5' tRNA fragment.
    Genes Dev. (IF 8.99) 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 8.99) 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 8.99) 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 8.99) 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 8.99) 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 8.99) 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 8.99) 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 8.99) 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 8.99) 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 8.99) 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 8.99) 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 8.99) 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 8.99) 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 8.99) 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 8.99) 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 8.99) 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
  • A single-cell atlas of the developing Drosophila ovary identifies follicle stem cell progenitors.
    Genes Dev. (IF 8.99) Pub Date : 2020-01-09
    Maija Slaidina,Torsten U Banisch,Selena Gupta,Ruth Lehmann

    Addressing the complexity of organogenesis at a system-wide level requires a complete understanding of adult cell types, their origin, and precursor relationships. The Drosophila ovary has been a model to study how coordinated stem cell units, germline, and somatic follicle stem cells maintain and renew an organ. However, lack of cell type-specific tools have limited our ability to study the origin

    更新日期:2020-01-09
  • The microtubule regulator ringer functions downstream from the RNA repair/splicing pathway to promote axon regeneration.
    Genes Dev. (IF 8.99) Pub Date : 2020-01-09
    Ernest J Monahan Vargas,Andrew J Matamoros,Jingyun Qiu,Calvin H Jan,Qin Wang,David Gorczyca,Tina W Han,Jonathan S Weissman,Yuh Nung Jan,Swati Banerjee,Yuanquan Song

    Promoting axon regeneration in the central and peripheral nervous system is of clinical importance in neural injury and neurodegenerative diseases. Both pro- and antiregeneration factors are being identified. We previously reported that the Rtca mediated RNA repair/splicing pathway restricts axon regeneration by inhibiting the nonconventional splicing of Xbp1 mRNA under cellular stress. However, the

    更新日期:2020-01-09
  • Hap2-Ino80-facilitated transcription promotes de novo establishment of CENP-A chromatin.
    Genes Dev. (IF 8.99) Pub Date : 2020-01-09
    Puneet P Singh,Manu Shukla,Sharon A White,Marcel Lafos,Pin Tong,Tatsiana Auchynnikava,Christos Spanos,Juri Rappsilber,Alison L Pidoux,Robin C Allshire

    Centromeres are maintained epigenetically by the presence of CENP-A, an evolutionarily conserved histone H3 variant, which directs kinetochore assembly and hence centromere function. To identify factors that promote assembly of CENP-A chromatin, we affinity-selected solubilized fission yeast CENP-ACnp1 chromatin. All subunits of the Ino80 complex were enriched, including the auxiliary subunit Hap2

    更新日期:2020-01-09
  • Upon microbial challenge, human neutrophils undergo rapid changes in nuclear architecture and chromatin folding to orchestrate an immediate inflammatory gene program.
    Genes Dev. (IF 8.99) Pub Date : 2020-01-09
    Matthew Denholtz,Yina Zhu,Zhaoren He,Hanbin Lu,Takeshi Isoda,Simon Döhrmann,Victor Nizet,Cornelis Murre

    Differentiating neutrophils undergo large-scale changes in nuclear morphology. How such alterations in structure are established and modulated upon exposure to microbial agents is largely unknown. Here, we found that prior to encounter with bacteria, an armamentarium of inflammatory genes was positioned in a transcriptionally passive environment suppressing premature transcriptional activation. Upon

    更新日期:2020-01-09
  • The chromatin remodeler Snf2h is essential for oocyte meiotic cell cycle progression.
    Genes Dev. (IF 8.99) Pub Date : 2020-01-09
    Chunxia Zhang,Zhiyuan Chen,Qiangzong Yin,Xudong Fu,Yisi Li,Tomas Stopka,Arthur I Skoultchi,Yi Zhang

    Oocytes are indispensable for mammalian life. Thus, it is important to understand how mature oocytes are generated. As a critical stage of oocytes development, meiosis has been extensively studied, yet how chromatin remodeling contributes to this process is largely unknown. Here, we demonstrate that the ATP-dependent chromatin remodeling factor Snf2h (also known as Smarca5) plays a critical role in

    更新日期:2020-01-09
  • Corrigendum: DNA polymerase θ accomplishes translesion synthesis opposite 1,N6-ethenodeoxyadenosine with a remarkably high fidelity in human cells.
    Genes Dev. (IF 8.99) Pub Date : 2020-01-01
    Jung-Hoon Yoon,Robert E Johnson,Louise Prakash,Satya Prakash

    Genes & Development 33: 282–287 (2019)

    更新日期:2020-01-02
  • Reviewers, Volume 33 (2019)
    Genes Dev. (IF 8.99) Pub Date : 2019-12-01

    The editors would like to thank the Editorial Board and the following scientists who reviewed papers and provided advice during 2019.

    更新日期:2019-12-03
  • Erratum: Single-nucleus transcriptomic survey of cell diversity and functional maturation in postnatal mammalian hearts
    Genes Dev. (IF 8.99) Pub Date : 2019-11-01
    Peng Hu; Jian Liu; Juanjuan Zhao; Benjamin J. Wilkins; Katherine Lupino; Hao Wu; Liming Pei

    Genes & Development 32: 1344–1357 (2018)

    更新日期:2019-11-01
  • Erratum: Dedifferentiation by adenovirus E1A due to inactivation of Hippo pathway effectors YAP and TAZ
    Genes Dev. (IF 8.99) Pub Date : 2019-11-01
    Nathan R. Zemke; Dawei Gou; Arnold J. Berk

    Genes & Development 33: 828–843 (2019)

    更新日期:2019-11-01
  • The human nucleolus organizer regions.
    Genes Dev. (IF 8.99) Pub Date : 2019-12-01
    Joseph G Gall

    Although the nucleolus was first described in the early 19th century from both animal and plant cells, human nucleoli and particularly the five human nucleolus organizers have not been well characterized. In this issue of Genes & Development, van Sluis and colleagues (pp. 1688-1701) present a detailed molecular analysis of these organizers, which occur on the short arms of five human chromosomes. The

    更新日期:2019-11-01
  • Mixed ubiquitin chains regulate DNA repair.
    Genes Dev. (IF 8.99) Pub Date : 2019-12-01
    Gergely Rona,Michele Pagano

    Diverse linkage in polyubiquitin chain structure gives cells an unparalleled complexity to virtually modulate all aspects of cell biology. Substrates can be covalently modified by ubiquitin chains of different topology. Proper DNA damage response takes advantage of this regulatory system and heavily relies on ubiquitin-based signaling. Moreover, increasing evidence suggests that chain specificity dictates

    更新日期:2019-11-01
  • Paralytic, the Drosophila voltage-gated sodium channel, regulates proliferation of neural progenitors.
    Genes Dev. (IF 8.99) Pub Date : 2019-11-21
    Beverly J Piggott,Christian J Peters,Ye He,Xi Huang,Susan Younger,Lily Yeh Jan,Yuh Nung Jan

    Proliferating cells, typically considered "nonexcitable," nevertheless, exhibit regulation by bioelectric signals. Notably, voltage-gated sodium channels (VGSC) that are crucial for neuronal excitability are also found in progenitors and up-regulated in cancer. Here, we identify a role for VGSC in proliferation of Drosophila neuroblast (NB) lineages within the central nervous system. Loss of paralytic

    更新日期:2019-11-01
  • Systematic bromodomain protein screens identify homologous recombination and R-loop suppression pathways involved in genome integrity.
    Genes Dev. (IF 8.99) Pub Date : 2019-11-21
    Jae Jin Kim,Seo Yun Lee,Fade Gong,Anna M Battenhouse,Daniel R Boutz,Aarti Bashyal,Samantha T Refvik,Cheng-Ming Chiang,Blerta Xhemalce,Tanya T Paull,Jennifer S Brodbelt,Edward M Marcotte,Kyle M Miller

    Bromodomain proteins (BRD) are key chromatin regulators of genome function and stability as well as therapeutic targets in cancer. Here, we systematically delineate the contribution of human BRD proteins for genome stability and DNA double-strand break (DSB) repair using several cell-based assays and proteomic interaction network analysis. Applying these approaches, we identify 24 of the 42 BRD proteins

    更新日期:2019-11-01
  • Activation of invariant natural killer T cells stimulates adipose tissue remodeling via adipocyte death and birth in obesity.
    Genes Dev. (IF 8.99) Pub Date : 2019-11-14
    Jeu Park,Jin Young Huh,Jiyoung Oh,Jong In Kim,Sang Mun Han,Kyung Cheul Shin,Yong Geun Jeon,Sung Sik Choe,Jiyoung Park,Jae Bum Kim

    In obesity, adipose tissue undergoes dynamic remodeling processes such as adipocyte hypertrophy, hypoxia, immune responses, and adipocyte death. However, whether and how invariant natural killer T (iNKT) cells contribute to adipose tissue remodeling are elusive. In this study, we demonstrate that iNKT cells remove unhealthy adipocytes and stimulate the differentiation of healthy adipocytes. In obese

    更新日期:2019-11-01
  • Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity.
    Genes Dev. (IF 8.99) Pub Date : 2019-11-14
    Haruki Horiguchi,Tsuyoshi Kadomatsu,Ryoma Kurahashi,Chiaki Hara,Keishi Miyata,Masaya Baba,Hironobu Osumi,Kazutoyo Terada,Kimi Araki,Toshiyuki Takai,Tomomi Kamba,W Marston Linehan,Toshiro Moroishi,Yuichi Oike

    Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein homologous to angiopoietins. Previous studies suggest that tumor cell-derived ANGPTL2 has tumor-promoting function. Here, we conducted mechanistic analysis comparing ANGPTL2 function in cancer progression in a murine syngeneic model of melanoma and a mouse model of translocation renal cell carcinoma (tRCC). ANGPTL2 deficiency in tumor

    更新日期:2019-11-01
  • Human NORs, comprising rDNA arrays and functionally conserved distal elements, are located within dynamic chromosomal regions.
    Genes Dev. (IF 8.99) Pub Date : 2019-11-14
    Marjolein van Sluis,Michael Ó Gailín,Joseph G W McCarter,Hazel Mangan,Alice Grob,Brian McStay

    Human nucleolar organizer regions (NORs), containing ribosomal gene (rDNA) arrays, are located on the p-arms of acrocentric chromosomes (HSA13-15, 21, and 22). Absence of these p-arms from genome references has hampered research on nucleolar formation. Previously, we assembled a distal junction (DJ) DNA sequence contig that abuts rDNA arrays on their telomeric side, revealing that it is shared among

    更新日期:2019-11-01
  • The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis.
    Genes Dev. (IF 8.99) Pub Date : 2019-11-14
    Matthew G Oser,Amin H Sabet,Wenhua Gao,Abhishek A Chakraborty,Anna C Schinzel,Rebecca B Jennings,Raquel Fonseca,Dennis M Bonal,Matthew A Booker,Abdallah Flaifel,Jesse S Novak,Camilla L Christensen,Hua Zhang,Zachary T Herbert,Michael Y Tolstorukov,Elizabeth J Buss,Kwok-Kin Wong,Roderick T Bronson,Quang-De Nguyen,Sabina Signoretti,William G Kaelin

    More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1 The canonical function of the RB1 gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes

    更新日期:2019-11-01
  • Crosstalk between Lys63- and Lys11-polyubiquitin signaling at DNA damage sites is driven by Cezanne.
    Genes Dev. (IF 8.99) Pub Date : 2019-11-07
    Xiao Wu,Shichang Liu,Cari Sagum,Jianji Chen,Rajesh Singh,Apurva Chaturvedi,John R Horton,Tanuja R Kashyap,David Fushman,Xiaodong Cheng,Mark T Bedford,Bin Wang

    The establishment of polyubiquitin conjugates with distinct linkages play important roles in the DNA damage response. Much remains unknown about the regulation of linkage-specific ubiquitin signaling at sites of DNA damage. Here we reveal that Cezanne (also known as Otud7B) deubiquitinating enzyme promotes the recruitment of Rap80/BRCA1-A complex by binding to Lys63-polyubiquitin and targeting Lys11-polyubiquitin

    更新日期:2019-11-01
  • Context-specific regulation of cell survival by a miRNA-controlled BIM rheostat.
    Genes Dev. (IF 8.99) Pub Date : 2019-11-07
    Verena Labi,Siying Peng,Filippos Klironomos,Mathias Munschauer,Nicolai Kastelic,Tirtha Chakraborty,Katia Schoeler,Emmanuel Derudder,Manuela Martella,Guido Mastrobuoni,Luis R Hernandez-Miranda,Ines Lahmann,Christine Kocks,Carmen Birchmeier,Stefan Kempa,Leticia Quintanilla-Martinez de Fend,Markus Landthaler,Nikolaus Rajewsky,Klaus Rajewsky

    Knockout of the ubiquitously expressed miRNA-17∼92 cluster in mice produces a lethal developmental lung defect, skeletal abnormalities, and blocked B lymphopoiesis. A shared target of miR-17∼92 miRNAs is the pro-apoptotic protein BIM, central to life-death decisions in mammalian cells. To clarify the contribution of miR-17∼92:Bim interactions to the complex miR-17∼92 knockout phenotype, we used a system

    更新日期:2019-11-01
  • Hippo signaling does it again: arbitrating cardiac fibroblast identity and activation.
    Genes Dev. (IF 8.99) Pub Date : 2019-11-05
    Anne Katrine Z Johansen,Jeffery D Molkentin

    The Hippo pathway is an evolutionarily conserved kinase cascade that is fundamental for tissue development, homeostasis, and regeneration. In the developing mammalian heart, Hippo signaling regulates cardiomyocyte numbers and organ size. While cardiomyocytes in the adult heart are largely postmitotic, Hippo deficiency can increase proliferation of these cells and affect cardiac regenerative capacity

    更新日期:2019-11-01
  • Human stem cell models: lessons for pancreatic development and disease.
    Genes Dev. (IF 8.99) Pub Date : 2019-11-01
    Bjoern Gaertner,Andrea C Carrano,Maike Sander

    A comprehensive understanding of mechanisms that underlie the development and function of human cells requires human cell models. For the pancreatic lineage, protocols have been developed to differentiate human pluripotent stem cells (hPSCs) into pancreatic endocrine and exocrine cells through intermediates resembling in vivo development. In recent years, this differentiation system has been employed

    更新日期:2019-11-01
  • Metabolic dependencies and vulnerabilities in leukemia.
    Genes Dev. (IF 8.99) Pub Date : 2019-11-01
    Marissa Rashkovan,Adolfo Ferrando

    Leukemia cell proliferation requires up-regulation and rewiring of metabolic pathways to feed anabolic cell growth. Oncogenic drivers directly and indirectly regulate metabolic pathways, and aberrant metabolism is central not only for leukemia proliferation and survival, but also mediates oncogene addiction with significant implications for the development of targeted therapies. This review explores

    更新日期:2019-11-01
  • Cell-type-specific dysregulation of RNA alternative splicing in short tandem repeat mouse knockin models of myotonic dystrophy.
    Genes Dev. (IF 8.99) Pub Date : 2019-10-17
    Curtis A Nutter,Jodi L Bubenik,Ruan Oliveira,Franjo Ivankovic,Łukasz J Sznajder,Benjamin M Kidd,Belinda S Pinto,Brittney A Otero,Helmut A Carter,Eric A Vitriol,Eric T Wang,Maurice S Swanson

    Short tandem repeats (STRs) are prone to expansion mutations that cause multiple hereditary neurological and neuromuscular diseases. To study pathomechanisms using mouse models that recapitulate the tissue specificity and developmental timing of an STR expansion gene, we used rolling circle amplification and CRISPR/Cas9-mediated genome editing to generate Dmpk CTG expansion (CTGexp) knockin models

    更新日期:2019-11-01
  • Checkpoint inhibition of origin firing prevents DNA topological stress.
    Genes Dev. (IF 8.99) Pub Date : 2019-10-17
    Esther C Morafraile,Christine Hänni,George Allen,Theresa Zeisner,Caroline Clarke,Mark C Johnson,Miguel M Santos,Lauren Carroll,Nicola E Minchell,Jonathan Baxter,Peter Banks,Dave Lydall,Philip Zegerman

    A universal feature of DNA damage and replication stress in eukaryotes is the activation of a checkpoint-kinase response. In S-phase, the checkpoint inhibits replication initiation, yet the function of this global block to origin firing remains unknown. To establish the physiological roles of this arm of the checkpoint, we analyzed separation of function mutants in the budding yeast Saccharomyces cerevisiae

    更新日期:2019-11-01
  • Hi-C guided assemblies reveal conserved regulatory topologies on X and autosomes despite extensive genome shuffling.
    Genes Dev. (IF 8.99) Pub Date : 2019-10-10
    Gina Renschler,Gautier Richard,Claudia Isabelle Keller Valsecchi,Sarah Toscano,Laura Arrigoni,Fidel Ramírez,Asifa Akhtar

    Genome rearrangements that occur during evolution impose major challenges on regulatory mechanisms that rely on three-dimensional genome architecture. Here, we developed a scaffolding algorithm and generated chromosome-length assemblies from Hi-C data for studying genome topology in three distantly related Drosophila species. We observe extensive genome shuffling between these species with one synteny

    更新日期:2019-11-01
  • Evaluating phase separation in live cells: diagnosis, caveats, and functional consequences.
    Genes Dev. (IF 8.99) Pub Date : 2019-10-08
    David T McSwiggen,Mustafa Mir,Xavier Darzacq,Robert Tjian

    The idea that liquid-liquid phase separation (LLPS) may be a general mechanism by which molecules in the complex cellular milieu may self-organize has generated much excitement and fervor in the cell biology community. While this concept is not new, its rise to preeminence has resulted in renewed interest in the mechanisms that shape and drive diverse cellular self-assembly processes from gene expression

    更新日期:2019-11-01
  • Intricate SUMO-based control of the homologous recombination machinery.
    Genes Dev. (IF 8.99) Pub Date : 2019-10-03
    Nalini Dhingra,Xiaolan Zhao

    The homologous recombination (HR) machinery plays multiple roles in genome maintenance. Best studied in the context of DNA double-stranded break (DSB) repair, recombination enzymes can cleave, pair, and unwind DNA molecules, and collaborate with regulatory proteins to execute multiple DNA processing steps before generating specific repair products. HR proteins also help to cope with problems arising

    更新日期:2019-11-01
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