2. Academic Validation
  3. DNA Ligase IV regulates XRCC4 nuclear localization

DNA Ligase IV regulates XRCC4 nuclear localization

  • DNA Repair (Amst). 2014 Sep;21:36-42. doi: 10.1016/j.dnarep.2014.05.010.
Dailia B Francis 1,  Mikhail Kozlov 2,  Jose Chavez 2,  Jennifer Chu 2,  Shruti Malu 2,  Mary Hanna 2,  Patricia Cortes 3
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
PMID: 24984242 DOI: 10.1016/j.dnarep.2014.05.010
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.

Keywords

DNA Ligase IV; DNA repair; NHEJ; V(D)J recombination; XRCC4.

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