title: Akt-mediated phosphorylation of XLF impairs non-homologous end-joining DNA repair.
abstract: Deficiency in repair of damaged DNA leads to genomic instability and is closely associated with tumorigenesis. Most DNA double-strand-breaks (DSBs) are repaired by two major mechanisms, homologous-recombination (HR) and non-homologous-end-joining (NHEJ). Although Akt has been reported to suppress HR, its role in NHEJ remains elusive. Here, we report that Akt phosphorylates XLF at Thr181 to trigger its dissociation from the DNA ligase IV/XRCC4 complex, and promotes its interaction with 14-3-3β leading to XLF cytoplasmic retention, where cytosolic XLF is subsequently degraded by SCF(β-TRCP) in a CKI-dependent manner. Physiologically, upon DNA damage, XLF-T181E expressing cells display impaired NHEJ and elevated cell death. Whereas a cancer-patient-derived XLF-R178Q mutant, deficient in XLF-T181 phosphorylation, exhibits an elevated tolerance of DNA damage. Together, our results reveal a pivotal role for Akt in suppressing NHEJ and highlight the tight connection between aberrant Akt hyper-activation and deficiency in timely DSB repair, leading to genomic instability and tumorigenesis.
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Pengda
authors: P
authors: Liu
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Wenjian
authors: W
authors: Gan
authors: Howeard Hughes Medical Institute, the Children's Hospital, the Immune Disease Institute and Harvard Medical School, Boston, MA 02115, USA.
authors: Chunguang
authors: C
authors: Guo
authors: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China.
authors: Anyong
authors: A
authors: Xie
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Daming
authors: D
authors: Gao
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Jianping
authors: J
authors: Guo
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Jinfang
authors: J
authors: Zhang
authors: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors: Nicholas
authors: N
authors: Willis
authors: Howeard Hughes Medical Institute, the Children's Hospital, the Immune Disease Institute and Harvard Medical School, Boston, MA 02115, USA.
authors: Arthur
authors: A
authors: Su
authors: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors: John M
authors: JM
authors: Asara
authors: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors: Ralph
authors: R
authors: Scully
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: wwei2@bidmc.harvard.edu.
authors: Wenyi
authors: W
authors: Wei
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000595:Amino Acid Sequence; D063646:Carcinogenesis / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000235:genetics*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D042822:Genomic Instability; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology*; D044843:SKP Cullin F-Box Protein Ligases / Q000502:physiology; D016415:Sequence Alignment
chemical_list: D048948:14-3-3 Proteins; D004268:DNA-Binding Proteins; C000607893:LIG4 protein, human; C508551:NHEJ1 protein, human; C101467:XRCC4 protein, human; C482982:YWHAB protein, human; D044843:SKP Cullin F-Box Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D011088:DNA Ligases; D045643:DNA Repair Enzymes; D000072481:DNA Ligase ATP