title: Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways.
abstract: Fanconi anemia (FA) and ataxia telangiectasia (AT) are clinically distinct autosomal recessive disorders characterized by spontaneous chromosome breakage and hematological cancers. FA cells are hypersensitive to mitomycin C (MMC), while AT cells are hypersensitive to ionizing radiation (IR). Here, we identify the Fanconi anemia protein, FANCD2, as a link between the FA and ATM damage response pathways. ATM phosphorylates FANCD2 on serine 222 in vitro. This site is also phosphorylated in vivo in an ATM-dependent manner following IR. Phosphorylation of FANCD2 is required for activation of an S phase checkpoint. The ATM-dependent phosphorylation of FANCD2 on S222 and the FA pathway-dependent monoubiquitination of FANCD2 on K561 are independent posttranslational modifications regulating discrete cellular signaling pathways. Biallelic disruption of FANCD2 results in both MMC and IR hypersensitivity.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Irene
authors.initials: I
authors.lastname: Garcia-Higuera
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.forename: Paul R
authors.initials: PR
authors.lastname: Andreassen
authors.forename: Richard C
authors.initials: RC
authors.lastname: Gregory
authors.forename: Seong-Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: William S
authors.initials: WS
authors.lastname: Lane
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kastan
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004268:DNA-Binding Proteins; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D052236:Fanconi Anemia Complementation Group D2 Protein; D016193:G1 Phase / Q000187:drug effects / Q000528:radiation effects; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D018816:Genes, cdc / Q000187:drug effects / Q000528:radiation effects; D006367:HeLa Cells; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D009154:Mutation / Q000187:drug effects / Q000528:radiation effects; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000528:radiation effects; D010768:Phosphoserine / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D016196:S Phase / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D010768:Phosphoserine; D016685:Mitomycin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases