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Tytuł:
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A Cancer-Specific Ubiquitin Ligase Drives mRNA Alternative Polyadenylation by Ubiquitinating the mRNA 3' End Processing Complex.
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Autorzy:
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Yang SW; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Li L; Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA; Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Connelly JP; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Porter SN; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Kodali K; Departments of Structural Biology and Developmental Neurobiology, Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Gan H; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Park JM; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Tacer KF; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Tillman H; Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Peng J; Departments of Structural Biology and Developmental Neurobiology, Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Pruett-Miller SM; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Li W; Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA; Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Potts PR; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: .
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Źródło:
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Molecular cell [Mol Cell] 2020 Mar 19; Vol. 77 (6), pp. 1206-1221.e7. Date of Electronic Publication: 2020 Jan 21.
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Typ publikacji:
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Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Cambridge Ma : Cell Press
Original Publication: Cambridge, Mass. : Cell Press, c1997-
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MeSH Terms:
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3' Untranslated Regions/*genetics
Antigens, Neoplasm/*metabolism
Lung Neoplasms/*pathology
Neoplasm Proteins/*metabolism
Ovarian Neoplasms/*pathology
RNA, Messenger/*metabolism
Ubiquitin/*metabolism
mRNA Cleavage and Polyadenylation Factors/*metabolism
Animals ; Antigens, Neoplasm/genetics ; Apoptosis ; Biomarkers, Tumor ; Carcinogenesis ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/metabolism ; Carcinoma, Squamous Cell/pathology ; Cell Proliferation ; Cleavage And Polyadenylation Specificity Factor/genetics ; Cleavage And Polyadenylation Specificity Factor/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neoplasm Proteins/genetics ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Polyadenylation ; RNA Splicing ; RNA, Messenger/genetics ; Tumor Cells, Cultured ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination ; Xenograft Model Antitumor Assays ; mRNA Cleavage and Polyadenylation Factors/genetics
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Grant Information:
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15-0177 United Kingdom AICR_ Worldwide Cancer Research; R01 CA193466 United States CA NCI NIH HHS
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Contributed Indexing:
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Keywords: 3′ UTR shortening; 3′ end processing complex; CFIm25; HUWE1; MAGE-A11; PCF11; PTEN; alternative polyadenylation; cyclin D2; ubiquitin
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Substance Nomenclature:
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0 (3' Untranslated Regions)
0 (Antigens, Neoplasm)
0 (Biomarkers, Tumor)
0 (Cleavage And Polyadenylation Specificity Factor)
0 (MAGEA11 protein, human)
0 (Neoplasm Proteins)
0 (Nudt21 protein, human)
0 (Pcf11 protein, human)
0 (RNA, Messenger)
0 (Tumor Suppressor Proteins)
0 (Ubiquitin)
0 (mRNA Cleavage and Polyadenylation Factors)
EC 2.3.2.26 (HUWE1 protein, human)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
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Entry Date(s):
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Date Created: 20200126 Date Completed: 20200714 Latest Revision: 20210121
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Update Code:
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20240104
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DOI:
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10.1016/j.molcel.2019.12.022
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PMID:
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31980388
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Alternative polyadenylation (APA) contributes to transcriptome complexity by generating mRNA isoforms with varying 3' UTR lengths. APA leading to 3' UTR shortening (3' US) is a common feature of most cancer cells; however, the molecular mechanisms are not understood. Here, we describe a widespread mechanism promoting 3' US in cancer through ubiquitination of the mRNA 3' end processing complex protein, PCF11, by the cancer-specific MAGE-A11-HUWE1 ubiquitin ligase. MAGE-A11 is normally expressed only in the male germline but is frequently re-activated in cancers. MAGE-A11 is necessary for cancer cell viability and is sufficient to drive tumorigenesis. Screening for targets of MAGE-A11 revealed that it ubiquitinates PCF11, resulting in loss of CFIm25 from the mRNA 3' end processing complex. This leads to APA of many transcripts affecting core oncogenic and tumor suppressors, including cyclin D2 and PTEN. These findings provide insights into the molecular mechanisms driving APA in cancer and suggest therapeutic strategies.
Competing Interests: Declaration of Interests The authors declare no competing interests.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
