title: WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response.
abstract: Genomic instability is a hallmark of cancer. The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of γ-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel;
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abu-Odeh
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Al Quds-Bard College, Al-Quds University, Abu Dies, East Jerusalem; and.
authors.forename: Zaidoun
authors.initials: Z
authors.lastname: Salah
authors.affiliation: German Cancer Research Center, Cellular Senescence Group, German Cancer Research Center-Zentrum für Molekulare Biologie der Universität Heidelberg Alliance, 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Herbel
authors.affiliation: German Cancer Research Center, Cellular Senescence Group, German Cancer Research Center-Zentrum für Molekulare Biologie der Universität Heidelberg Alliance, 69120 Heidelberg, Germany.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hofmann
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; ramiaq@ekmd.huji.ac.il.
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D004260:DNA Repair; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: C468783:H2AX protein, human; D006657:Histones; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C475961:gamma-H2AX protein, mouse; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C428130:Wwox protein, mouse; C432966:ITCH protein, human; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse
keywords: ITCH; WW domain-containing oxidoreductase; ataxia telangiectasia-mutated; common fragile sites; genomic instability