184 results match your criteria suppressors enhancers

The landscape and driver potential of site-specific hotspots across cancer genomes.

NPJ Genom Med 2021 May 13;6(1):33. Epub 2021 May 13.

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.

Large sets of whole cancer genomes make it possible to study mutation hotspots genome-wide. Here we detect, categorize, and characterize site-specific hotspots using 2279 whole cancer genomes from the Pan-Cancer Analysis of Whole Genomes project and provide a resource of annotated hotspots genome-wide. We investigate the excess of hotspots in both protein-coding and gene regulatory regions and develop measures of positive selection and functional impact for individual hotspots. Read More

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Genome-wide RNAi screen for regulators of UPRmt in Caenorhabditis elegans mutants with defects in mitochondrial fusion.

G3 (Bethesda) 2021 Mar 30. Epub 2021 Mar 30.

Faculty of Biology, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany.

Mitochondrial dynamics plays an important role in mitochondrial quality control and the adaptation of metabolic activity in response to environmental changes. The disruption of mitochondrial dynamics has detrimental consequences for mitochondrial and cellular homeostasis and leads to the activation of the mitochondrial unfolded protein response (UPRmt), a quality control mechanism that adjusts cellular metabolism and restores homeostasis. To identify genes involved in the induction of UPRmt in response to a block in mitochondrial fusion, we performed a genome-wide RNAi screen in Caenorhabditis elegans mutants lacking the gene fzo-1, which encodes the ortholog of mammalian Mitofusin, and identified 299 suppressors and 86 enhancers. Read More

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Integrative pan cancer analysis reveals epigenomic variation in cancer type and cell specific chromatin domains.

Nat Commun 2021 03 3;12(1):1419. Epub 2021 Mar 3.

Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.

Epigenetic mechanisms contribute to the initiation and development of cancer, and epigenetic variation promotes dynamic gene expression patterns that facilitate tumor evolution and adaptation. While the NCI-60 panel represents a diverse set of human cancer cell lines that has been used to screen chemical compounds, a comprehensive epigenomic atlas of these cells has been lacking. Here, we report an integrative analysis of 60 human cancer epigenomes, representing a catalog of activating and repressive histone modifications. Read More

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Comprehensive characterisation of intronic mis-splicing mutations in human cancers.

Oncogene 2021 Feb 8;40(7):1347-1361. Epub 2021 Jan 8.

Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, Republic of Korea.

Previous studies studying mis-splicing mutations were based on exome data and thus our current knowledge is largely limited to exons and the canonical splice sites. To comprehensively characterise intronic mis-splicing mutations, we analysed 1134 pan-cancer whole genomes and transcriptomes together with 3022 normal control samples. The ratio-based splicing analysis resulted in 678 somatic intronic mutations, with 46% residing in deep introns. Read More

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February 2021

Overexpression of FKH-2/FOXG1 is neuroprotective in a C. elegans model of Machado-Joseph disease.

Exp Neurol 2021 Mar 5;337:113544. Epub 2020 Dec 5.

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900 St-Denis Street, Montreal, Quebec H2X 0A9, Canada; Department of Biochemistry, University of Montreal, 2900 Edouard Montpetit Blvd, Montreal, Quebec H3T 1J4, Canada; Department of Neuroscience, University of Montreal, 2900 Edouard Montpetit Blvd, Montreal, Quebec H3T 1J4, Canada. Electronic address:

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is the most common form of dominantly inherited ataxia worldwide. This disease is caused by an expanded CAG repeat in the coding region of ATXN3. Due to our incomplete understanding of mechanisms and molecular pathways related to this disease, there are no therapies that successfully treat core MJD patients. Read More

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Genetic interactions among ADAMTS metalloproteases and basement membrane molecules in cell migration in Caenorhabditis elegans.

PLoS One 2020 2;15(12):e0240571. Epub 2020 Dec 2.

Department of Bioscience, Kwansei Gakuin University, Sanda, Japan.

During development of the Caenorhabditis elegans gonad, the gonadal leader cells, called distal tip cells (DTCs), migrate in a U-shaped pattern to form the U-shaped gonad arms. The ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family metalloproteases MIG-17 and GON-1 are required for correct DTC migration. Mutations in mig-17 result in misshapen gonads due to the misdirected DTC migration, and mutations in gon-1 result in shortened and swollen gonads due to the premature termination of DTC migration. Read More

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January 2021

A Genetic Screen to Identify New Molecular Players Involved in Photoprotection qH in .

Plants (Basel) 2020 Nov 13;9(11). Epub 2020 Nov 13.

Umeå Plant Science Centre, Department of Plant Physiology, Umeå University, 901 87 Umeå, Sweden.

Photosynthesis is a biological process which converts light energy into chemical energy that is used in the Calvin-Benson cycle to produce organic compounds. An excess of light can induce damage to the photosynthetic machinery. Therefore, plants have evolved photoprotective mechanisms such as non-photochemical quenching (NPQ). Read More

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November 2020

Endogenous retroviruses drive KRAB zinc-finger protein family expression for tumor suppression.

Sci Adv 2020 Oct 21;6(43). Epub 2020 Oct 21.

Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 1088639, Japan.

Gene expression aberration is a hallmark of cancers, but the mechanisms underlying such aberrations remain unclear. Human endogenous retroviruses (HERVs) are genomic repetitive elements that potentially function as enhancers. Since numerous HERVs are epigenetically activated in tumors, their activation could cause global gene expression aberrations in tumors. Read More

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October 2020

The Branched Nature of the Nonsense-Mediated mRNA Decay Pathway.

Trends Genet 2021 02 29;37(2):143-159. Epub 2020 Sep 29.

Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA; Center for RNA Biology, The Ohio State University, Columbus, OH 43210, USA. Electronic address:

Nonsense-mediated mRNA decay (NMD) is a conserved translation-coupled quality control mechanism in all eukaryotes that regulates the expression of a significant fraction of both the aberrant and normal transcriptomes. In vertebrates, NMD has become an essential process owing to expansion of the diversity of NMD-regulated transcripts, particularly during various developmental processes. Surprisingly, however, some core NMD factors that are essential for NMD in simpler organisms appear to be dispensable for vertebrate NMD. Read More

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February 2021

Exploiting Drosophila melanogaster Wing Imaginal Disc Eversion to Screen for New EMT Effectors.

Methods Mol Biol 2021 ;2179:115-134

School of BioSciences, University of Melbourne, Parkville, VIC, Australia.

In the early stages of Drosophila melanogaster (Drosophila) metamorphosis, a partial epithelial-mesenchymal transition (pEMT) takes place in the peripodial epithelium of wing imaginal discs. Blocking this pEMT results in adults with internalized wings and missing thoracic tissue. Using peripodial GAL4 drivers, GAL80 temporal control, and UAS RNAi transgenes, one can use these phenotypes to screen for genes involved in the pEMT. Read More

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The Yin and Yang function of microRNAs in insulin signalling and cancer.

RNA Biol 2021 01 13;18(1):24-32. Epub 2020 Aug 13.

National Clinical Research Center for Metabolic Diseases, and Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University , Changsha, China.

Data accumulated over the past several decades uncover a vital role of microRNAs (miRNAs) in various biological processes. It is well established that, by binding to target mRNAs, miRNAs act as post-transcription suppressors to inhibit mRNA translation and/or to promote mRNA degradation. Very recently, miRNAs have been found to act as positive regulators to promote gene transcription. Read More

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January 2021

A simple and highly efficient method for multi-allelic CRISPR-Cas9 editing in primary cell cultures.

Cancer Rep (Hoboken) 2020 10 28;3(5):e1269. Epub 2020 Jul 28.

Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Background: CRISPR-Cas9-based technologies have revolutionized experimental manipulation of mammalian genomes. None-the-less, limitations of the delivery and efficacy of these technologies restrict their application in primary cells.

Aims: To create an optimized protocol for penetrant, reproducible, and fast targeted genome editing in cell cultures derived from primary cells, using patient-derived glioblastoma stem-like cells (GSCs) and human neural stem/progenitor cells (NSCs) for proof-of-concept experiments. Read More

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October 2020

Prolyl Isomerase Pin1 in Human Cancer: Function, Mechanism, and Significance.

Front Cell Dev Biol 2020 31;8:168. Epub 2020 Mar 31.

Laboratory of Molecular Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University Collaborative Innovation Center of Biotherapy, Chengdu, China.

Peptidyl-prolyl isomerase NIMA-interacting 1 (Pin1) is an evolutionally conserved and unique enzyme that specifically catalyzes the isomerization of phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif and, subsequently, induces the conformational change of its substrates. Mounting evidence has demonstrated that Pin1 is widely overexpressed and/or overactivated in cancer, exerting a critical influence on tumor initiation and progression via regulation of the biological activity, protein degradation, or nucleus-cytoplasmic distribution of its substrates. Moreover, Pin1 participates in the cancer hallmarks through activating some oncogenes and growth enhancers, or inactivating some tumor suppressors and growth inhibitors, suggesting that Pin1 could be an attractive target for cancer therapy. Read More

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Salinomycin-Loaded Iron Oxide Nanoparticles for Glioblastoma Therapy.

Nanomaterials (Basel) 2020 Mar 6;10(3). Epub 2020 Mar 6.

Department of Biomedical Engineering, University of Manitoba, Winnipeg, MB R3T 5V6, Canada.

Salinomycin is an antibiotic introduced recently as a new and effective anticancer drug. In this study, magnetic iron oxide nanoparticles (IONPs) were utilized as a drug carrier for salinomycin for potential use in glioblastoma (GBM) chemotherapy. The biocompatible polyethylenimine (PEI)-polyethylene glycol (PEG)-IONPs (PEI-PEG-IONPs) exhibited an efficient uptake in both mouse brain-derived microvessel endothelial (bEnd. Read More

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Epstein-Barr virus-positive gastric cancer involves enhancer activation through activating transcription factor 3.

Cancer Sci 2020 May 20;111(5):1818-1828. Epub 2020 Mar 20.

Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Epstein-Barr virus (EBV) is associated with particular forms of gastric cancer (GC). We previously showed that EBV infection into gastric epithelial cells induced aberrant DNA hypermethylation in promoter regions and silencing of tumor suppressor genes. We here undertook integrated analyses of transcriptome and epigenome alteration during EBV infection in gastric cells, to investigate activation of enhancer regions and related transcription factors (TFs) that could contribute to tumorigenesis. Read More

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TOPORS, a tumor suppressor protein, contributes to the maintenance of higher-order chromatin architecture.

Biochim Biophys Acta Gene Regul Mech 2020 05 27;1863(5):194518. Epub 2020 Feb 27.

The Fifth People's Hospital of Shanghai, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai 200438, China. Electronic address:

In the nucleus, chromosomes are hierarchically folded into active (A) and inactive (B) compartments composed of topologically associating domains (TADs). Genomic regions interact with nuclear lamina, termed lamina-associated domains (LADs). However, the molecular mechanisms underlying these 3D chromatin architectures remain incompletely understood. Read More

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Targeting Oncogenic Super Enhancers in MYC-Dependent AML Using a Small Molecule Activator of NR4A Nuclear Receptors.

Sci Rep 2020 02 18;10(1):2851. Epub 2020 Feb 18.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.

Epigenetic reprogramming in Acute Myeloid Leukemia (AML) leads to the aberrant activation of super enhancer (SE) landscapes that drive the expression of key oncogenes, including the oncogenic MYC pathway. These SEs have been identified as promising therapeutic targets, and have given rise to a new class of drugs, including BET protein inhibitors, which center on targeting SE activity. NR4A nuclear receptors are tumor suppressors of AML that function in part through transcriptional repression of the MYC-driven oncogenic program via mechanisms that remain unclear. Read More

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February 2020

Druggable genome screen identifies new regulators of the abundance and toxicity of ATXN3, the Spinocerebellar Ataxia type 3 disease protein.

Neurobiol Dis 2020 04 26;137:104697. Epub 2019 Nov 26.

Department of Neurology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Spinocerebellar Ataxia type 3 (SCA3, also known as Machado-Joseph disease) is a neurodegenerative disorder caused by a CAG repeat expansion encoding an abnormally long polyglutamine (polyQ) tract in the disease protein, ataxin-3 (ATXN3). No preventive treatment is yet available for SCA3. Because SCA3 is likely caused by a toxic gain of ATXN3 function, a rational therapeutic strategy is to reduce mutant ATXN3 levels by targeting pathways that control its production or stability. Read More

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Pharmaco-Genetic Screen To Uncover Actin Regulators Targeted by Prostaglandins During Oogenesis.

G3 (Bethesda) 2019 11 5;9(11):3555-3565. Epub 2019 Nov 5.

Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242

Prostaglandins (PGs) are lipid signaling molecules with numerous physiologic functions, including pain/inflammation, fertility, and cancer. PGs are produced downstream of cyclooxygenase (COX) enzymes, the targets of non-steroidal anti-inflammatory drugs (NSAIDs). In numerous systems, PGs regulate actin cytoskeletal remodeling, however, their mechanisms of action remain largely unknown. Read More

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November 2019

Identification of Enhancers Activated by TGFβ to Drive Expression of and in HeLa Cells.

Mol Cancer Res 2019 09 12;17(9):1854-1866. Epub 2019 Jun 12.

Division of Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.

Disruption of the () and () genes, which encode three function-independent tumor suppressors, is one of the most common events in human cancer. Because their relative importance in tumor prevention appears to be species- and context-specific, studying their regulation can shed light on mechanisms by which they are bypassed in malignant transformation. We previously unveiled a new pathway in which TGFβ selectively induces at mouse in eye development and cultured fibroblasts. Read More

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September 2019

Chemical enhancers of posttranscriptional gene silencing in .

RNA 2019 09 4;25(9):1078-1090. Epub 2019 Jun 4.

Department of Biology, Swiss Federal Institute of Technology (ETH Zürich), 8092 Zürich, Switzerland.

RNAi mediated by small-interfering RNAs (siRNAs) operates via transcriptional (TGS) and posttranscriptional gene silencing (PTGS). In , TGS relies on DICER-LIKE-3 (DCL3)-dependent 24-nt siRNAs loaded into AGO4-clade ARGONAUTE effector proteins. PTGS operates via DCL4-dependent 21-nt siRNAs loaded into AGO1-clade proteins. Read More

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September 2019

Incompatibilities in Mismatch Repair Genes Contribute to a Wide Range of Mutation Rates in Human Isolates of Baker's Yeast.

Genetics 2018 12 22;210(4):1253-1266. Epub 2018 Oct 22.

Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853-2703

Laboratory baker's yeast strains bearing an incompatible combination of and mismatch repair alleles are mutators that can adapt more rapidly to stress, but do so at the cost of long-term fitness. We identified 18 baker's yeast isolates from 1011 surveyed that contain the incompatible genotype in a heterozygous state. Surprisingly, the incompatible combination from two human clinical heterozygous diploid isolates, YJS5845 and YJS5885, contain the exact (S288c-derived) and (SK1-derived) open reading frames originally shown to confer incompatibility. Read More

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December 2018

The Molecular Basis of Metastatic Colorectal Cancer.

Curr Colorectal Cancer Rep 2018 Apr 1;14(2):69-79. Epub 2018 Mar 1.

Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Purpose Of Review: Metastatic colorectal cancer (CRC) is a vexing clinical problem. In contrast to early stage disease, once CRC metastasizes to other organs, long-term survival is compromised. We seek to review the molecular pathogenesis, animal models, and functional genomics for an enhanced understanding of how CRC metastasizes and how this can be exploited therapeutically. Read More

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Zebrafish blastomere screen identifies retinoic acid suppression of in adenoid cystic carcinoma.

J Exp Med 2018 10 12;215(10):2673-2685. Epub 2018 Sep 12.

Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA

Pluripotent cells have been used to probe developmental pathways that are involved in genetic diseases and oncogenic events. To find new therapies that would target -driven tumors, we developed a pluripotent zebrafish blastomere culture system. We performed a chemical genetic screen and identified retinoic acid agonists as suppressors of expression. Read More

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October 2018

The Tandem Duplicator Phenotype Is a Prevalent Genome-Wide Cancer Configuration Driven by Distinct Gene Mutations.

Cancer Cell 2018 08 12;34(2):197-210.e5. Epub 2018 Jul 12.

The Jackson Laboratory, Bar Harbor, ME 04609, USA. Electronic address:

The tandem duplicator phenotype (TDP) is a genome-wide instability configuration primarily observed in breast, ovarian, and endometrial carcinomas. Here, we stratify TDP tumors by classifying their tandem duplications (TDs) into three span intervals, with modal values of 11 kb, 231 kb, and 1.7 Mb, respectively. Read More

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Microcystin-LR reduces the synthesis of gonadotropin-releasing hormone by activating multiple signaling pathways resulting in decrease of testosterone in mice.

Sci Total Environ 2018 Dec 23;643:496-506. Epub 2018 Jun 23.

Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China. Electronic address:

We previously reported Microcystin-LR (MC-LR) could enter the hypothalamus, reduce the expression of gonadotropin-releasing hormone (GnRH), and induce male reproductive barriers. However, the molecular mechanisms underlying in the hypothalamus have not been elucidated in detail. In this study, we further showed that MC-LR inhibited the synthesis of GnRH in GnRH neurons via activating protein kinase a (PKA), cAMP-response element binding protein (Creb), protein kinase c (PKC), nuclear factor kappa B (NF-κB), extracellular regulated protein kinases (Erk) and P38 protein, and thus resulted in the change of activity of transcriptional enhancers or suppressors such as Oct-1, Otx-2, Pbx1a, Dlx-2, c-Jun and c-Fos. Read More

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December 2018

KDM1A microenvironment, its oncogenic potential, and therapeutic significance.

Epigenetics Chromatin 2018 06 19;11(1):33. Epub 2018 Jun 19.

KNU-Center for Nonlinear Dynamics, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu, 41566, South Korea.

The lysine-specific histone demethylase 1A (KDM1A) was the first demethylase to challenge the concept of the irreversible nature of methylation marks. KDM1A, containing a flavin adenine dinucleotide (FAD)-dependent amine oxidase domain, demethylates histone 3 lysine 4 and histone 3 lysine 9 (H3K4me1/2 and H3K9me1/2). It has emerged as an epigenetic developmental regulator and was shown to be involved in carcinogenesis. Read More

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Insight into Notch Signaling Steps That Involve from Dominant-Modifier Screens in .

Genetics 2018 08 31;209(4):1099-1119. Epub 2018 May 31.

Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka 560-0043, Japan

Notch signaling plays crucial roles in intercellular communications. In , the () gene, which encodes an evolutionarily conserved multi-pass transmembrane protein, appears to be required to activate Notch signaling in some contexts, especially during neuroblast segregation in the neuroectoderm. Although Pcx has been suggested to contribute to endoplasmic reticulum homeostasis, its functions remain unknown. Read More

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Emerging roles of long non-coding RNA in cancer.

Cancer Sci 2018 Jul 28;109(7):2093-2100. Epub 2018 Jun 28.

Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.

Since comprehensive analysis of the mammalian genome revealed that the majority of genomic products are transcribed in long non-coding RNA (lncRNA), increasing attention has been paid to these transcripts. The applied next-generation sequencing technologies have provided accumulating evidence of dysregulated lncRNA in cancer. The implication of this finding can be seen in many forms and at multiple levels. Read More

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The Pentatricopeptide Repeat Protein SOT5/EMB2279 Is Required for Plastid and Intron Splicing.

Plant Physiol 2018 06 23;177(2):684-697. Epub 2018 Apr 23.

Department of Biology, College of Life and Environmental Sciences, Shanghai Normal University, Shanghai 200234, China

Chloroplast biogenesis and development are highly complex processes requiring interaction between plastid and nuclear genomic products. Using a high-throughput screen for chloroplast biogenesis suppressors in Arabidopsis (), we identified a () that displays virescent and serrated leaves. Further characterization revealed that mutants are defective in leaf adaxial and abaxial polarity and act as enhancers of Map-based cloning identified as a gene previously named that encodes a plastid-targeted pentatricopeptide repeat (PPR) protein with 11 PPR motifs. Read More

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