title: DNA-dependent targeting of cell nuclei by a lupus autoantibody.
abstract: A nuclear-penetrating lupus anti-DNA autoantibody, 3E10, has been found to inhibit DNA repair and selectively kill certain cancer cells that are highly vulnerable to DNA damage. In addition, a 3E10 single chain variable fragment (scFv) has been developed for use as a delivery vehicle to carry therapeutic cargo proteins into cell nuclei. A greater understanding of the mechanism by which 3E10 penetrates cell nuclei is needed to help determine the scope of its potential therapeutic applications. Here we show that the presence of extracellular DNA significantly enhances the nuclear uptake of 3E10 scFv. In addition, we find that 3E10 scFv preferentially localizes into tumor cell nuclei in vivo, likely due to increased DNA in the local environment released from ischemic and necrotic regions of tumor. These data provide insight into the mechanism of nuclear penetration by 3E10 and demonstrate the potential for use of 3E10 in therapeutic approaches to diseases ranging from malignancy to ischemic conditions such as stroke.
authors.affiliation: Department of Research, Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA 91343.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Weisbart
authors.affiliation: Department of Research, Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA 91343.
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.affiliation: Department of Research, Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA 91343.
authors.forename: Gwen
authors.initials: G
authors.lastname: Jordaan
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Noble
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1] Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520 [2] Department of Genetics, Yale School of Medicine, New Haven, CT 06520 [3] Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Glazer
authors.affiliation: 1] Department of Research, Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA 91343 [2] Department of Neurology, University of California, Los Angeles, CA 90095.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Nishimura
authors.affiliation: 1] Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520 [2] Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520.
authors.forename: James E
authors.initials: JE
authors.lastname: Hansen
mesh_terms: D000974:Antibodies, Antinuclear / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000276:immunology* / Q000378:metabolism*; D004247:DNA / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D021381:Protein Transport; D057127:Single-Chain Antibodies / Q000276:immunology / Q000378:metabolism
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D057127:Single-Chain Antibodies; D004247:DNA