title: Nedd4 family interacting protein 1 (Ndfip1) is required for ubiquitination and nuclear trafficking of BRCA1-associated ATM activator 1 (BRAT1) during the DNA damage response.
abstract: During injury, cells are vulnerable to apoptosis from a variety of stress conditions including DNA damage causing double-stranded breaks. Without repair, these breaks lead to aberrations in DNA replication and transcription, leading to apoptosis. A major response to DNA damage is provided by the protein kinase ATM (ataxia telangiectasia mutated) that is capable of commanding a plethora of signaling networks for DNA repair, cell cycle arrest, and even apoptosis. A key element in the DNA damage response is the mobilization of activating proteins into the cell nucleus to repair damaged DNA. BRAT1 is one of these proteins, and it functions as an activator of ATM by maintaining its phosphorylated status while also keeping other phosphatases at bay. However, it is unknown how BRAT1 is trafficked into the cell nucleus to maintain ATM phosphorylation. Here we demonstrate that Ndfip1-mediated ubiquitination of BRAT1 leads to BRAT1 trafficking into the cell nucleus. Without Ndfip1, BRAT1 failed to translocate to the nucleus. Under genotoxic stress, cells showed increased expression of both Ndfip1 and phosphorylated ATM. Following brain injury, neurons show increased expression of Ndfip1 and nuclear translocation of BRAT1. These results point to Ndfip1 as a sensor protein during cell injury and Ndfip1 up-regulation as a cue for BRAT1 ubiquitination by Nedd4 E3 ligases, followed by nuclear translocation of BRAT1.
authors: From the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, 3010 Victoria, Australia.
authors: Ley-Hian
authors: LH
authors: Low
authors: From the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, 3010 Victoria, Australia.
authors: Yuh-Lit
authors: YL
authors: Chow
authors: From the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, 3010 Victoria, Australia.
authors: Yijia
authors: Y
authors: Li
authors: From the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, 3010 Victoria, Australia.
authors: Choo-Peng
authors: CP
authors: Goh
authors: From the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, 3010 Victoria, Australia.
authors: Ulrich
authors: U
authors: Putz
authors: the Walter & Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, 3010 Victoria, Australia, and.
authors: John
authors: J
authors: Silke
authors: the Department of Cancer Genetics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York 14263.
authors: Toru
authors: T
authors: Ouchi
authors: From the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, 3010 Victoria, Australia, jhowitt@florey.edu.au.
authors: Jason
authors: J
authors: Howitt
authors: From the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, 3010 Victoria, Australia, stan@florey.edu.au.
authors: Seong-Seng
authors: SS
authors: Tan
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D001930:Brain Injuries / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D000075702:Nedd4 Ubiquitin Protein Ligases; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D059748:Proteolysis; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C573230:BRAT1 protein, human; C000597968:BRAT1 protein, mouse; D002352:Carrier Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C451223:NDFIP1 protein, human; C499188:Ndfip1 protein, mouse; D009687:Nuclear Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: DNA Damage Response; Intracellular Trafficking; Neuroprotection; Nuclear Transport; Ubiquitylation (ubiquitination)
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