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Dmitri Pervouchine, Yaroslav Popov, Andy Berry, Beatrice Borsari, Adam Frankish, Roderic Guigó
Nonsense-mediated decay (NMD) is a eukaryotic mRNA surveillance system that selectively degrades transcripts with premature termination codons (PTC). Many RNA-binding proteins (RBP) regulate their expression levels by a negative feedback loop, in which RBP binds its own pre-mRNA and causes alternative splicing to introduce a PTC. We present a bioinformatic analysis integrating three data sources, eCLIP assays for a large RBP panel, shRNA inactivation of NMD pathway, and shRNA-depletion of RBPs followed by RNA-seq, to identify novel such autoregulatory feedback loops...
March 27, 2019: Nucleic Acids Research
Rozario Thomas, Ravindra Majeti
A report in this issue of Cancer Cell identifies the RNA-binding protein RBM39 as a potential target in spliceosome mutant AML that can be targeted by existing sulfonamide drugs. These results support a proposed clinical trial in patients with myeloid malignancies bearing spliceosome mutations relapsed or refractory to standard therapy.
March 18, 2019: Cancer Cell
Eric Wang, Sydney X Lu, Alessandro Pastore, Xufeng Chen, Jochen Imig, Stanley Chun-Wei Lee, Kathryn Hockemeyer, Yohana E Ghebrechristos, Akihide Yoshimi, Daichi Inoue, Michelle Ki, Hana Cho, Lillian Bitner, Andreas Kloetgen, Kuan-Ting Lin, Taisuke Uehara, Takashi Owa, Raoul Tibes, Adrian R Krainer, Omar Abdel-Wahab, Iannis Aifantis
RNA-binding proteins (RBPs) are essential modulators of transcription and translation frequently dysregulated in cancer. We systematically interrogated RBP dependencies in human cancers using a comprehensive CRISPR/Cas9 domain-focused screen targeting RNA-binding domains of 490 classical RBPs. This uncovered a network of physically interacting RBPs upregulated in acute myeloid leukemia (AML) and crucial for maintaining RNA splicing and AML survival. Genetic or pharmacologic targeting of one key member of this network, RBM39, repressed cassette exon inclusion and promoted intron retention within mRNAs encoding HOXA9 targets as well as in other RBPs preferentially required in AML...
February 4, 2019: Cancer Cell
Jana Královicová, Ivana Ševcíková, Eva Stejskalová, Mina Obuca, Michael Hiller, David Stanek, Igor Vorechovský
PUF60 is a splicing factor that binds uridine (U)-rich tracts and facilitates association of the U2 small nuclear ribonucleoprotein with primary transcripts. PUF60 deficiency (PD) causes a developmental delay coupled with intellectual disability and spinal, cardiac, ocular and renal defects, but PD pathogenesis is not understood. Using RNA-Seq, we identify human PUF60-regulated exons and show that PUF60 preferentially acts as their activator. PUF60-activated internal exons are enriched for Us upstream of their 3' splice sites (3'ss), are preceded by longer AG dinucleotide exclusion zones and more distant branch sites, with a higher probability of unpaired interactions across a typical branch site location as compared to control exons...
July 6, 2018: Nucleic Acids Research
(no author information available yet)
Anticancer sulfonamides produce aberrant splicing by inducing degradation of the splicing factor RBM39.
May 12, 2017: Cancer Discovery
Ting Han, Maria Goralski, Nicholas Gaskill, Emanuela Capota, Jiwoong Kim, Tabitha C Ting, Yang Xie, Noelle S Williams, Deepak Nijhawan
Indisulam is an aryl sulfonamide drug with selective anticancer activity. Its mechanism of action and the basis for its selectivity have so far been unknown. Here we show that indisulam promotes the recruitment of RBM39 (RNA binding motif protein 39) to the CUL4-DCAF15 E3 ubiquitin ligase, leading to RBM39 polyubiquitination and proteasomal degradation. Mutations in RBM39 that prevent its recruitment to CUL4-DCAF15 increase RBM39 stability and confer resistance to indisulam's cytotoxicity. RBM39 associates with precursor messenger RNA (pre-mRNA) splicing factors, and inactivation of RBM39 by indisulam causes aberrant pre-mRNA splicing...
April 28, 2017: Science
Shu-Ching Huang, Henry S Zhang, Brian Yu, Ellen McMahon, Dan T Nguyen, Faye H Yu, Alexander C Ou, Jennie Park Ou, Edward J Benz
Exon 16 of protein 4.1R encodes a spectrin/actin-binding peptide critical for erythrocyte membrane stability. Its expression during erythroid differentiation is regulated by alternative pre-mRNA splicing. A UUUUCCCCCC motif situated between the branch point and the 3' splice site is crucial for inclusion. We show that the UUUU region and the last three C residues in this motif are necessary for the binding of splicing factors TIA1 and Pcbp1 and that these proteins appear to act in a collaborative manner to enhance exon 16 inclusion...
May 1, 2017: Molecular and Cellular Biology
Douglas M Anderson, Jessica Cannavino, Hui Li, Kelly M Anderson, Benjamin R Nelson, John McAnally, Svetlana Bezprozvannaya, Yun Liu, Weichun Lin, Ning Liu, Rhonda Bassel-Duby, Eric N Olson
Innervation of skeletal muscle by motor neurons occurs through the neuromuscular junction, a cholinergic synapse essential for normal muscle growth and function. Defects in nerve-muscle signaling cause a variety of neuromuscular disorders with features of ataxia, paralysis, skeletal muscle wasting, and degeneration. Here we show that the nuclear zinc finger protein ZFP106 is highly enriched in skeletal muscle and is required for postnatal maintenance of myofiber innervation by motor neurons. Genetic disruption of Zfp106 in mice results in progressive ataxia and hindlimb paralysis associated with motor neuron degeneration, severe muscle wasting, and premature death by 6 mo of age...
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
Sanyue Mai, Xiuhua Qu, Ping Li, Qingjun Ma, Cheng Cao, Xuan Liu
BACKGROUND: RBM39 is a serine/arginine-rich RNA-binding protein that is highly homologous to the splicing factor U2AF65. However, the role of RBM39 in alternative splicing is poorly understood. METHODS: In this study, RBM39-mediated global alternative splicing was investigated using RNA-Seq and genome-wide RBM39-RNA interactions were mapped via cross-linking and immunoprecipitation coupled with deep sequencing (CLIP-Seq) in wild-type and RBM39-knockdown MCF-7 cells...
August 2016: Biochimica et Biophysica Acta
Noel Faherty, Matthew Benson, Eshita Sharma, Angela Lee, Alison Howarth, Helen Lockstone, Daniel Ebner, Shoumo Bhattacharya
BMP signalling is negatively autoregulated by several genes including SMAD6, Noggin and Gremlin, and autoregulators are possible targets for enhancing BMP signalling in disorders such as fibrosis and pulmonary hypertension. To identify novel negative regulators of BMP signalling, we used siRNA screening in mouse C2C12 cells with a BMP-responsive luciferase reporter. Knockdown of several splicing factors increased BMP4-dependent transcription and target gene expression. Knockdown of RBM39 produced the greatest enhancement in BMP activity...
June 21, 2016: Scientific Reports
Galina A Stepanyuk, Pedro Serrano, Eigen Peralta, Carol L Farr, Herbert L Axelrod, Michael Geralt, Debanu Das, Hsiu-Ju Chiu, Lukasz Jaroszewski, Ashley M Deacon, Scott A Lesley, Marc-André Elsliger, Adam Godzik, Ian A Wilson, Kurt Wüthrich, Daniel R Salomon, James R Williamson
RNA-binding protein 39 (RBM39) is a splicing factor and a transcriptional co-activator of estrogen receptors and Jun/AP-1, and its function has been associated with malignant progression in a number of cancers. The C-terminal RRM domain of RBM39 belongs to the U2AF homology motif family (UHM), which mediate protein-protein interactions through a short tryptophan-containing peptide known as the UHM-ligand motif (ULM). Here, crystal and solution NMR structures of the RBM39-UHM domain, and the crystal structure of its complex with U2AF65-ULM, are reported...
April 2016: Acta Crystallographica. Section D, Structural Biology
Sanyue Mai, Xiuhua Qu, Ping Li, Qingjun Ma, Xuan Liu, Cheng Cao
RBM39, also known as splicing factor HCC1.4, acts as a transcriptional coactivator for the steroid nuclear receptors JUN/AP-1, ESR1/ER-α and ESR2/ER-β. RBM39 is involved in the regulation of the transcriptional responses of these steroid nuclear receptors and promotes transcriptional initiation. In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis...
April 22, 2016: Biochemical and Biophysical Research Communications
Jessica M Skeie, Vinit B Mahajan
IMPORTANCE: Differences in geographical protein expression in the human choroid-retinal pigment epithelial (RPE) complex may explain molecular predisposition of regions to ophthalmic diseases such as age-related macular degeneration. OBJECTIVE: To characterize the proteome of the human choroid-RPE complex and to identify differentially expressed proteins in specific anatomic regions. DESIGN, SETTING, AND PARTICIPANTS: Experimental study of choroid-RPE tissue from 3 nondiseased eyes...
November 2014: JAMA Ophthalmology
Anke H Sillars-Hardebol, Beatriz Carvalho, Jeroen A M Beliën, Meike de Wit, Pien M Delis-van Diemen, Marianne Tijssen, Mark A van de Wiel, Fredrik Pontén, Gerrit A Meijer, Remond J A Fijneman
BACKGROUND: Gain of chromosome 20q is an important factor in the progression from colorectal adenomas to carcinomas. Genes that drive 20q gain are expected to show correlation of mRNA and protein expression levels with 20q DNA copy number status while functionally influencing cancer processes. CSE1L, DIDO1 and RBM39 are located on the 20q amplicon and affect processes such as cell viability and anchorage-independent growth in colorectal cancer. This study aimed to investigate whether CSE1L, DIDO1 and RBM39 may drive 20q amplification...
August 2012: Cellular Oncology (Dordrecht)
Anke H Sillars-Hardebol, Beatriz Carvalho, Marianne Tijssen, Jeroen A M Beliën, Meike de Wit, Pien M Delis-van Diemen, Fredrik Pontén, Mark A van de Wiel, Remond J A Fijneman, Gerrit A Meijer
BACKGROUND AND OBJECTIVE: Progression of a colorectal adenoma to invasive cancer occurs in a minority of adenomas and is the most crucial step in colorectal cancer pathogenesis. In the majority of cases, this is associated with gain of a substantial part of chromosome 20q, indicating that multiple genes on the 20q amplicon may drive carcinogenesis. The aim of this study was to identify genes located on the 20q amplicon that promote progression of colorectal adenoma to carcinoma. DESIGN: Functional assays were performed for 32 candidate driver genes for which a positive correlation between 20q DNA copy number and mRNA expression had been demonstrated...
November 2012: Gut
Angelica Nordin, Elin Larsson, Monica Holmberg
Hereditary myopathy with lactic acidosis (HML) is caused by an intron mutation in the iron-sulfur cluster assembly gene ISCU, which leads to the activation of cryptic splice sites and the retention of part of intron 4. This incorrect splicing is more pronounced in muscle than in other tissues, resulting in a muscle-specific phenotype. In this study, we identified five nuclear factors that interact with the sequence harboring the mutation and analyzed their effect on the splicing of the ISCU gene. The identification revealed three splicing factors, SFRS14, RBM39, and PTBP1, and two additional RNA binding factors, matrin 3 (MATR3) and IGF2BP1...
March 2012: Human Mutation
Justin R Prigge, Sonya V Iverson, Ashley M Siders, Edward E Schmidt
U2 small nuclear ribonucleoprotein auxiliary factor (U2AF) is an essential component of the splicing machinery that is composed of two protein subunits, the 35 kDa U2AF(35) (U2AF1) and the 65 kDa U2AF(65) (U2AF2). U2AF interacts with various splicing factors within this machinery. Here we expand the list of mammalian splicing factors that are known to interact with U2AF(65) as well as the list of nuclear proteins not known to participate in splicing that interact with U2AF(65). Using a yeast two-hybrid system, we found fourteen U2AF(65)-interacting proteins...
June 2009: Biochimica et Biophysica Acta
A Stratil, A Knoll, P Horák, K Bílek, R Bechynová, H Bartenschlager, M Van Poucke, L J Peelman, K Svobodová, H Geldermann
No abstract text is available yet for this article.
April 2008: Animal Genetics
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