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Genes & Development

Kohji Hizume, Shizuko Endo, Sachiko Muramatsu, Takehiko Kobayashi, Hiroyuki Araki
The proper pausing of replication forks at barriers on chromosomes is important for genome integrity. However, the detailed mechanism underlying this process has not been well elucidated. Here, we successfully reconstituted fork-pausing reactions from purified yeast proteins on templates that had binding sites for the LacI, LexA, and/or Fob1 proteins; the forks paused specifically at the protein-bound sites. Moreover, although the replicative helicase Cdc45-Mcm2-7-GINS (CMG) complex alone unwound the protein-bound templates, the unwinding of the LacI-bound site was impeded by the presence of a main leading strand DNA polymerase: polymerase ε (Polε)...
September 19, 2018: Genes & Development
Takeo Horie, Ryoko Horie, Kai Chen, Chen Cao, Masashi Nakagawa, Takehiro G Kusakabe, Noriyuki Satoh, Yasunori Sasakura, Michael Levine
The CNS of the protovertebrate Ciona intestinalis contains a single cluster of dopaminergic (DA) neurons, the coronet cells, which have been likened to the hypothalamus of vertebrates. Whole-embryo single-cell RNA sequencing (RNA-seq) assays identified Ptf1a as the most strongly expressed cell-specific transcription factor (TF) in DA/coronet cells. Knockdown of Ptf1a activity results in their loss, while misexpression results in the appearance of supernumerary DA/coronet cells. Photoreceptor cells and ependymal cells are the most susceptible to transformation, and both cell types express high levels of Meis Coexpression of both Ptf1a and Meis caused the wholesale transformation of the entire CNS into DA/coronet cells...
September 18, 2018: Genes & Development
Yao Wan, Anita K Hopper
The mitochondrial cytoplasmic surface serves as a processing site for numerous RNAs from budding yeast to metazoans. We report that budding yeast mitochondrial outer membrane (MOM) proteins that are subunits of the translocase of the outer mitochondrial membrane (Tom70 and Tom 22) and sorting and assembly machinery (Sam37) are required for efficient pretransfer RNA (pre-tRNA) splicing. Defective pre-tRNA splicing in MOM mutants is due not to loss of respiratory metabolism but instead inefficient targeting/tethering of tRNA splicing endonuclease (SEN) subunits to mitochondria...
September 18, 2018: Genes & Development
Asako McCloskey, Arkaitz Ibarra, Martin W Hetzer
The total number of nuclear pore complexes (NPCs) per nucleus varies greatly between different cell types and is known to change during cell differentiation and cell transformation. However, the underlying mechanisms that control how many nuclear transport channels are assembled into a given nuclear envelope remain unclear. Here, we report that depletion of the NPC basket protein Tpr, but not Nup153, dramatically increases the total NPC number in various cell types. This negative regulation of Tpr occurs via a phosphorylation cascade of extracellular signal-regulated kinase (ERK), the central kinase of the mitogen-activated protein kinase (MAPK) pathway...
September 18, 2018: Genes & Development
Karine Pozo, John D Minna, Jane E Johnson
No abstract text is available yet for this article.
September 1, 2018: Genes & Development
Michael J Smith, Eric E Bryant, Rodney Rothstein
During homologous recombination, cells must coordinate repair, DNA damage checkpoint signaling, and movement of chromosomal loci to facilitate homology search. In Saccharomyces cerevisiae , increased movement of damaged loci (local mobility) and undamaged loci (global mobility) precedes homolog pairing in mitotic cells. How cells modulate chromosome mobility in response to DNA damage remains unclear. Here, we demonstrate that global chromosome mobility is regulated by the Rad51 recombinase and its mediator, Rad52...
September 1, 2018: Genes & Development
Rasmus Siersbæk, Sanjeev Kumar, Jason S Carroll
Estrogen receptor α (ER) is the major driver of ∼75% of breast cancers, and multiple ER targeting drugs are routinely used clinically to treat patients with ER+ breast cancer. However, many patients relapse on these targeted therapies and ultimately develop metastatic and incurable disease, and understanding the mechanisms leading to drug resistance is consequently of utmost importance. It is now clear that, in addition to estrogens, ER function is modulated by other steroid receptors and multiple signaling pathways (e...
September 1, 2018: Genes & Development
Guocan Wang, Di Zhao, Denise J Spring, Ronald A DePinho
Despite the high long-term survival in localized prostate cancer, metastatic prostate cancer remains largely incurable even after intensive multimodal therapy. The lethality of advanced disease is driven by the lack of therapeutic regimens capable of generating durable responses in the setting of extreme tumor heterogeneity on the genetic and cell biological levels. Here, we review available prostate cancer model systems, the prostate cancer genome atlas, cellular and functional heterogeneity in the tumor microenvironment, tumor-intrinsic and tumor-extrinsic mechanisms underlying therapeutic resistance, and technological advances focused on disease detection and management...
September 1, 2018: Genes & Development
Laura M Agosto, Kristen W Lynch
Alternative splicing (AS) of pre-mRNAs is a ubiquitous process in mammals that is tightly regulated in a cell type- and cell state-dependent manner. However, the details of how splicing is regulated to impact specific cell fate decisions remains incompletely understood. A study by Yamazaki and colleagues (pp. 1161-1174) in this issue of Genes & Development provides exciting new insight into the role and regulation of splicing in the maintenance of pluripotency of human embryonic stem cells (hESCs). In brief, they show that AS of several genes is robustly regulated upon differentiation of hESCs...
September 1, 2018: Genes & Development
Zhengming Wang, Thomas J Hardcastle, Alex Canto Pastor, Wing Hin Yip, Shuoya Tang, David C Baulcombe
Tomato Dicer-like2 (slDCL2) is a key component of resistance pathways against potato virus X (PVX) and tobacco mosaic virus (TMV). It is also required for production of endogenous small RNAs, including miR6026 and other noncanonical microRNAs (miRNAs). The slDCL 2 mRNAs are targets of these slDCL2-dependent RNAs in a feedback loop that was disrupted by target mimic RNAs of miR6026. In lines expressing these RNAs, there was correspondingly enhanced resistance against PVX and TMV. These findings illustrate a novel miRNA pathway in plants and a crop protection strategy in which miRNA target mimicry elevates expression of defense-related mRNAs...
September 1, 2018: Genes & Development
Benjamin Erickson, Ryan M Sheridan, Michael Cortazar, David L Bentley
Paused RNA polymerase II (Pol II) that piles up near most human promoters is the target of mechanisms that control entry into productive elongation. Whether paused Pol II is a stable or dynamic target remains unresolved. We report that most 5' paused Pol II throughout the genome is turned over within 2 min. This process is revealed under hypertonic conditions that prevent Pol II recruitment to promoters. This turnover requires cell viability but is not prevented by inhibiting transcription elongation, suggesting that it is mediated at the level of termination...
September 1, 2018: Genes & Development
Christine Chiasson-MacKenzie, Zachary S Morris, Ching-Hui Liu, William B Bradford, Thijs Koorman, Andrea I McClatchey
The architectural and biochemical features of the plasma membrane are governed by its intimate association with the underlying cortical cytoskeleton. The neurofibromatosis type 2 (NF2) tumor suppressor merlin and closely related membrane:cytoskeleton-linking protein ezrin organize the membrane:cytoskeleton interface, a critical cellular compartment that both regulates and is regulated by growth factor receptors. An example of this poorly understood interrelationship is macropinocytosis, an ancient process of nutrient uptake and membrane remodeling that can both be triggered by growth factors and manage receptor availability...
September 1, 2018: Genes & Development
Sida Liao, Ophélia Maertens, Karen Cichowski, Stephen J Elledge
Bromodomain and extraterminal (BET) domain inhibitors (BETis) show efficacy on NUT midline carcinoma (NMC). However, not all NMC patients respond, and responders eventually develop resistance and relapse. Using CRISPR and ORF expression screens, we systematically examined the ability of cancer drivers to mediate resistance of NMC to BETis and uncovered six general classes/pathways mediating resistance. Among these, we showed that RRAS2 attenuated the effect of JQ1 in part by sustaining ERK pathway function during BRD4 inhibition...
September 1, 2018: Genes & Development
Stephen D'Amico, Jiaqi Shi, Benjamin L Martin, Howard C Crawford, Oleksi Petrenko, Nancy C Reich
A dichotomy exists regarding the role of signal transducer and activator of transcription 3 (STAT3) in cancer. Functional and genetic studies demonstrate either an intrinsic requirement for STAT3 or a suppressive effect on common types of cancer. These contrasting actions of STAT3 imply context dependency. To examine mechanisms that underlie STAT3 function in cancer, we evaluated the impact of STAT3 activity in KRAS-driven lung and pancreatic cancer. Our study defines a fundamental and previously unrecognized function of STAT3 in the maintenance of epithelial cell identity and differentiation...
September 1, 2018: Genes & Development
Takashi Yamazaki, Lizhi Liu, Denis Lazarev, Amr Al-Zain, Vitalay Fomin, Percy Luk Yeung, Stuart M Chambers, Chi-Wei Lu, Lorenz Studer, James L Manley
Alternative splicing (AS) plays important roles in embryonic stem cell (ESC) differentiation. In this study, we first identified transcripts that display specific AS patterns in pluripotent human ESCs (hESCs) relative to differentiated cells. One of these encodes T-cell factor 3 (TCF3), a transcription factor that plays important roles in ESC differentiation. AS creates two TCF3 isoforms, E12 and E47, and we identified two related splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNPs) H1 and F (hnRNP H/F), that regulate TCF3 splicing...
September 1, 2018: Genes & Development
Maria Jessica Bruzzone, Sebastian Grünberg, Slawomir Kubik, Gabriel E Zentner, David Shore
The transcriptional coactivators Mediator and two histone acetyltransferase (HAT) complexes, NuA4 and SAGA, play global roles in transcriptional activation. Here we explore the relative contributions of these factors to RNA polymerase II association at specific genes and gene classes by rapid nuclear depletion of key complex subunits. We show that the NuA4 HAT Esa1 differentially affects certain groups of genes, whereas the SAGA HAT Gcn5 has a weaker but more uniform effect. Relative dependence on Esa1 and Tra1, a shared component of NuA4 and SAGA, distinguishes two large groups of coregulated growth-promoting genes...
September 1, 2018: Genes & Development
Alexandra Zinoviev, Akanksha Goyal, Supriya Jindal, John LaCava, Anton A Komar, Marina V Rodnina, Christopher U T Hellen, Tatyana V Pestova
GTP-binding protein 1 (GTPBP1) and GTPBP2 comprise a divergent group of translational GTPases with obscure functions, which are most closely related to eEF1A, eRF3, and Hbs1. Although recent reports implicated GTPBPs in mRNA surveillance and ribosome-associated quality control, how they perform these functions remains unknown. Here, we demonstrate that GTPBP1 possesses eEF1A-like elongation activity, delivering cognate aminoacyl-transfer RNA (aa-tRNA) to the ribosomal A site in a GTP-dependent manner. It also stimulates exosomal degradation of mRNAs in elongation complexes...
September 1, 2018: Genes & Development
Minchul Kim, Hagen Wende, Jan Walcher, Johannes Kühnemund, Cyril Cheret, Stefan Kempa, Erik McShane, Matthias Selbach, Gary R Lewis, Carmen Birchmeier
No abstract text is available yet for this article.
August 1, 2018: Genes & Development
Priya Chatterji, Kathryn E Hamilton, Shun Liang, Sarah F Andres, H R Sagara Wijeratne, Rei Mizuno, Lauren A Simon, Philip D Hicks, Shawn W Foley, Jason R Pitarresi, Andres J Klein-Szanto, Amanda T Mah, Laurianne Van Landeghem, Brian D Gregory, Christopher J Lengner, Blair B Madison, Premal Shah, Anil K Rustgi
RNA-binding proteins (RBPs) are expressed broadly during both development and malignant transformation, yet their mechanistic roles in epithelial homeostasis or as drivers of tumor initiation and progression are incompletely understood. Here we describe a novel interplay between RBPs LIN28B and IMP1 in intestinal epithelial cells. Ribosome profiling and RNA sequencing identified IMP1 as a principle node for gene expression regulation downstream from LIN28B In vitro and in vivo data demonstrate that epithelial IMP1 loss increases expression of WNT target genes and enhances LIN28B-mediated intestinal tumorigenesis, which was reversed when we overexpressed IMP1 independently in vivo...
August 1, 2018: Genes & Development
Ruthrothaselvi Bharathavikru, Nicholas D Hastie
Overgrowth syndromes such as Perlman syndrome and associated pediatric cancers, including Wilms tumor, arise through genetic and, in certain instances, also epigenetic changes. In the case of the Beckwith-Wiedemann overgrowth syndrome and in Wilms tumor, increased levels of IGF2 have been shown to be causally related to the disease manifestation. In the previous issue of Genes & Development , Hunter and colleagues (pp. 903-908) investigated the molecular mechanisms by which mutations in the gene encoding the RNA degradation component DIS3L2 lead to Perlman syndrome...
August 1, 2018: Genes & Development
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