title: WWOX modulates the ATR-mediated DNA damage checkpoint response.
abstract: For many decades genomic instability is considered one of the hallmarks of cancer. Role of the tumor suppressor WWOX (WW domain-containing oxidoreductase) in DNA damage response upon double strand breaks has been recently revealed. Here we demonstrate unforeseen functions for WWOX upon DNA single strand breaks (SSBs) checkpoint activation. We found that WWOX levels are induced following SSBs and accumulate in the nucleus. WWOX deficiency is associated with reduced activation of ataxia telangiectasia and Rad3-related protein (ATR) checkpoint proteins and increased chromosomal breaks. At the molecular level, we show that upon SSBs WWOX is modified at lysine 274 by ubiquitination mediated by the ubiquitin E3 ligase ITCH and interacts with ataxia telangiectasia-mutated (ATM). Interestingly, ATM inhibition was associated with reduced activation of ATR checkpoint proteins suggesting that WWOX manipulation of ATR checkpoint proteins is ATM-dependent. Taken together, the present findings indicate that WWOX plays a key role in ATR checkpoint activation, while its absence might facilitate genomic instability.
authors.affiliation: Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abu-Odeh
authors.affiliation: Department of Pathology, Immunology and Medical Genetics, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Hereema
authors.affiliation: Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.|Department of Molecular Virology, Immunology and Medical Genetics, Wexner Medical Center, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D061986:MCF-7 Cells; D051379:Mice; D018345:Mice, Knockout; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C428130:Wwox protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATR; ITCH; WWOX; common fragile sites; genomic instability