title: DNA Ligase IV regulates XRCC4 nuclear localization.
abstract: DNA Ligase IV, along with its interacting partner XRCC4, are essential for repairing DNA double strand breaks by non-homologous end joining (NHEJ). Together, they complete the final ligation step resolving the DNA break. Ligase IV is regulated by XRCC4 and XLF. However, the mechanism(s) by which Ligase IV control the NHEJ reaction and other NHEJ factor(s) remains poorly characterized. Here, we show that a C-terminal region of Ligase IV (aa 620-800), which encompasses a NLS, the BRCT I, and the XRCC4 interacting region (XIR), is essential for nuclear localization of its co-factor XRCC4. In Ligase IV deficient cells, XRCC4 showed deregulated localization remaining in the cytosol even after induction of DNA double strand breaks. DNA Ligase IV was also required for efficient localization of XLF into the nucleus. Additionally, human fibroblasts that harbor hypomorphic mutations within the Ligase IV gene displayed decreased levels of XRCC4 protein, implicating that DNA Ligase IV is also regulating XRCC4 stability. Our results provide evidence for a role of DNA Ligase IV in controlling the cellular localization and protein levels of XRCC4.
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Dailia B
authors.initials: DB
authors.lastname: Francis
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kozlov
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Jose
authors.initials: J
authors.lastname: Chavez
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chu
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Shruti
authors.initials: S
authors.lastname: Malu
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Hanna
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States; Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address: Patricia.Cortes@mssm.edu.
authors.forename: Patricia
authors.initials: P
authors.lastname: Cortes
mesh_terms: D021581:Active Transport, Cell Nucleus; D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D019913:Nuclear Localization Signals
chemical_list: D004268:DNA-Binding Proteins; C000607893:LIG4 protein, human; C508551:NHEJ1 protein, human; D019913:Nuclear Localization Signals; C101467:XRCC4 protein, human; D011088:DNA Ligases; D045643:DNA Repair Enzymes; D000072481:DNA Ligase ATP
keywords: DNA Ligase IV; DNA repair; NHEJ; V(D)J recombination; XRCC4