title: The viral oncoprotein tax sequesters DNA damage response factors by tethering MDC1 to chromatin.
abstract: Infection with human T-cell leukemia virus induces cellular genomic instability mediated through the viral oncoprotein Tax. Here we present evidence that Tax undermines the cellular DNA damage response by sequestration of damage response factors. We show by confocal microscopy that Tax forms damage-independent nuclear foci that contain DNA-PK, BRCA1, and MDC1. Tax sequesters MDC1 to chromatin sites distinct from classic ionizing radiation-induced foci. The recruitment of MDC1 is competitive between the two foci. The N-terminal region of Tax is sufficient for foci localization, and the C-terminal half is critical for binding to MDC1 and recruitment of additional response factors. Tax expression and DNA damage response factor recruitment repressed the formation of ionizing radiation-induced Nbs1-containing foci. The Tax-induced "pseudo" DNA damage response results in phosphorylation and monoubiquitylation of H2AX, which is ablated by siRNA suppression of MDC1. These data support a model for virus-induced genomic instability in which viral oncogene-induced damage-independent foci compete with normal cellular DNA damage response.
authors: From the Department of Microbiology and Molecular Cell Biology, Cancer Biology and Infectious Disease Research Center, Eastern Virginia Medical School, Norfolk, Virgina 23508.
authors: S Mehdi
authors: SM
authors: Belgnaoui
authors: From the Department of Microbiology and Molecular Cell Biology, Cancer Biology and Infectious Disease Research Center, Eastern Virginia Medical School, Norfolk, Virgina 23508.
authors: Kimberly A
authors: KA
authors: Fryrear
authors: From the Department of Microbiology and Molecular Cell Biology, Cancer Biology and Infectious Disease Research Center, Eastern Virginia Medical School, Norfolk, Virgina 23508.
authors: Julius O
authors: JO
authors: Nyalwidhe
authors: From the Department of Microbiology and Molecular Cell Biology, Cancer Biology and Infectious Disease Research Center, Eastern Virginia Medical School, Norfolk, Virgina 23508.
authors: Xin
authors: X
authors: Guo
authors: From the Department of Microbiology and Molecular Cell Biology, Cancer Biology and Infectious Disease Research Center, Eastern Virginia Medical School, Norfolk, Virgina 23508. Electronic address: Semmesoj@evms.edu.
authors: O John
authors: OJ
authors: Semmes
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics / Q000528:radiation effects; D011839:Radiation, Ionizing; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics / Q000528:radiation effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D016356:Gene Products, tax; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; C514970:tax protein, Human T-lymphotrophic virus 1; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human