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Tytuł:
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RNF8 Dysregulation and Down-regulation During HTLV-1 Infection Promote Genomic Instability in Adult T-Cell Leukemia.
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Autorzy:
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Zhi H; Department of Microbiology and Immunology Uniformed Services University of the Health Sciences Bethesda, MD, United States of America.
Guo X; Department of Microbiology and Molecular Cell Biology The Leroy T. Canoles Jr Cancer Research Center Eastern Virginia Medical School Norfolk, VA, United States of America.
Ho YK; Department of Microbiology and Immunology Uniformed Services University of the Health Sciences Bethesda, MD, United States of America.
Pasupala N; Department of Microbiology and Immunology Uniformed Services University of the Health Sciences Bethesda, MD, United States of America.
Engstrom HAA; Department of Microbiology and Molecular Cell Biology The Leroy T. Canoles Jr Cancer Research Center Eastern Virginia Medical School Norfolk, VA, United States of America.
Semmes OJ; Department of Microbiology and Molecular Cell Biology The Leroy T. Canoles Jr Cancer Research Center Eastern Virginia Medical School Norfolk, VA, United States of America.
Giam CZ; Department of Microbiology and Immunology Uniformed Services University of the Health Sciences Bethesda, MD, United States of America.
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Źródło:
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PLoS pathogens [PLoS Pathog] 2020 May 26; Vol. 16 (5), pp. e1008618. Date of Electronic Publication: 2020 May 26 (Print Publication: 2020).
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Typ publikacji:
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Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.
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Język:
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English
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Imprint Name(s):
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Original Publication: San Francisco, CA : Public Library of Science, c2005-
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MeSH Terms:
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DNA-Binding Proteins/*immunology
Down-Regulation/*immunology
Genomic Instability/*immunology
HTLV-I Infections/*immunology
Human T-lymphotropic virus 1/*immunology
Leukemia-Lymphoma, Adult T-Cell/*immunology
Neoplasm Proteins/*immunology
Ubiquitin-Protein Ligases/*immunology
DNA Breaks, Double-Stranded ; DNA Repair/genetics ; DNA Repair/immunology ; DNA-Binding Proteins/genetics ; Gene Products, tax/genetics ; Gene Products, tax/immunology ; HTLV-I Infections/genetics ; HTLV-I Infections/pathology ; HeLa Cells ; Human T-lymphotropic virus 1/genetics ; Humans ; Leukemia-Lymphoma, Adult T-Cell/genetics ; Leukemia-Lymphoma, Adult T-Cell/pathology ; Neoplasm Proteins/genetics ; Ubiquitin-Protein Ligases/genetics
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References:
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Grant Information:
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R21 CA216660 United States CA NCI NIH HHS
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Substance Nomenclature:
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0 (DNA-Binding Proteins)
0 (Gene Products, tax)
0 (Neoplasm Proteins)
0 (RNF8 protein, human)
0 (tax protein, Human T-lymphotrophic virus 1)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
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Entry Date(s):
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Date Created: 20200527 Date Completed: 20200721 Latest Revision: 20200721
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Update Code:
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20240105
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PubMed Central ID:
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PMC7274470
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DOI:
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10.1371/journal.ppat.1008618
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PMID:
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32453758
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The genomic instability associated with adult T cell leukemia/lymphoma (ATL) is causally linked to Tax, the HTLV-1 viral oncoprotein, but the underlying mechanism is not fully understood. We have previously shown that Tax hijacks and aberrantly activates ring finger protein 8 (RNF8) - a lysine 63 (K63)-specific ubiquitin E3 ligase critical for DNA double-strand break (DSB) repair signaling - to assemble K63-linked polyubiquitin chains (K63-pUbs) in the cytosol. Tax and the cytosolic K63-pUbs, in turn, initiate additional recruitment of linear ubiquitin assembly complex (LUBAC) to produce hybrid K63-M1 pUbs, which trigger a kinase cascade that leads to canonical IKK:NF-κB activation. Here we demonstrate that HTLV-1-infected cells are impaired in DNA damage response (DDR). This impairment correlates with the induction of microscopically visible nuclear speckles by Tax known as the Tax-speckle structures (TSS), which act as pseudo DNA damage signaling scaffolds that sequester DDR factors such as BRCA1, DNA-PK, and MDC1. We show that TSS co-localize with Tax, RNF8 and K63-pUbs, and their formation depends on RNF8. Tax mutants defective or attenuated in inducing K63-pUb assembly are deficient or tempered in TSS induction and DDR impairment. Finally, our results indicate that loss of RNF8 expression reduces HTLV-1 viral gene expression and frequently occurs in ATL cells. Thus, during HTLV-1 infection, Tax activates RNF8 to assemble nuclear K63-pUbs that sequester DDR factors in Tax speckles, disrupting DDR signaling and DSB repair. Down-regulation of RNF8 expression is positively selected during infection and progression to disease, and further exacerbates the genomic instability of ATL.
Competing Interests: The authors have declared that no competing interests exist.
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