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	Ley-Hian Low, Yuh-Lit Chow, Yijia Li, Choo-Peng Goh, Ulrich Putz, John Silke, Toru Ouchi, Jason Howitt, Seong-Seng Tan
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 11 Pg. 7141-50 (Mar 13 2015) ISSN: 1083-351X [Electronic] United States
PMID	25631046 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
Chemical References	BRAT1 protein, human BRAT1 protein, mouse Carrier Proteins Endosomal Sorting Complexes Required for Transport Intercellular Signaling Peptides and Proteins Membrane Proteins NDFIP1 protein, human Ndfip1 protein, mouse Nuclear Proteins Nedd4 Ubiquitin Protein Ligases Nedd4 protein, human Nedd4l protein, mouse Ubiquitin-Protein Ligases Ataxia Telangiectasia Mutated Proteins
Topics	Active Transport, Cell Nucleus Animals Ataxia Telangiectasia Mutated Proteins (metabolism) Brain Injuries (metabolism) Carrier Proteins (metabolism) Cell Line DNA Damage Endosomal Sorting Complexes Required for Transport (metabolism) HEK293 Cells Humans Intercellular Signaling Peptides and Proteins Membrane Proteins (metabolism) Mice, Inbred C57BL Nedd4 Ubiquitin Protein Ligases Nuclear Proteins (metabolism) Protein Binding Protein Interaction Mapping Protein Interaction Maps Proteolysis Signal Transduction Ubiquitin-Protein Ligases (metabolism) Ubiquitination

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