title: A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair.
abstract: When DNA replication is stalled at sites of DNA damage, a cascade of responses is activated in the cell to halt cell cycle progression and promote DNA repair. A pathway initiated by the kinase Ataxia teleangiectasia and Rad3 related (ATR) and its partner ATR interacting protein (ATRIP) plays an important role in this response. The Fanconi anemia (FA) pathway is also activated following genomic stress, and defects in this pathway cause a cancer-prone hematologic disorder in humans. Little is known about how these two pathways are coordinated. We report here that following cellular exposure to DNA cross-linking damage, the FA core complex enhances binding and localization of ATRIP within damaged chromatin. In cells lacking the core complex, ATR-mediated phosphorylation of two functional response targets, ATRIP and FANCI, is defective. We also provide evidence that the canonical ATR activation pathway involving RAD17 and TOPBP1 is largely dispensable for the FA pathway activation. Indeed DT40 mutant cells lacking both RAD17 and FANCD2 were synergistically more sensitive to cisplatin compared with either single mutant. Collectively, these data reveal new aspects of the interplay between regulation of ATR-ATRIP kinase and activation of the FA pathway.
authors.affiliation: Department of Late Effects Studies, Laboratory of DNA Damage Signaling, Kyoto University, Kyoto 606-8501, Japan, Japan Society for the Promotion of Science (JSPS), Tokyo 102-0083, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Tomida
authors.forename: Akiko
authors.initials: A
authors.lastname: Itaya
authors.forename: Tomoko
authors.initials: T
authors.lastname: Shigechi
authors.forename: Junya
authors.initials: J
authors.lastname: Unno
authors.forename: Emi
authors.initials: E
authors.lastname: Uchida
authors.forename: Masae
authors.initials: M
authors.lastname: Ikura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Masuda
authors.forename: Shun
authors.initials: S
authors.lastname: Matsuda
authors.forename: Jun
authors.initials: J
authors.lastname: Adachi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Amom Ruhikanta
authors.initials: AR
authors.lastname: Meetei
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Kamiya
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuura
authors.forename: Tomonari
authors.initials: T
authors.lastname: Matsuda
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ikura
authors.forename: Masamichi
authors.initials: M
authors.lastname: Ishiai
authors.forename: Minoru
authors.initials: M
authors.lastname: Takata
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry; D004260:DNA Repair; D004261:DNA Replication; D004277:DNA, Single-Stranded / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051716:Replication Protein A / Q000378:metabolism
chemical_list: C521194:ATRIP protein, human; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D002843:Chromatin; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D051716:Replication Protein A; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases