Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways.
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.
Taniguchi
Toshiyasu
T
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Garcia-Higuera
Irene
I
Xu
Bo
B
Andreassen
Paul R
PR
Gregory
Richard C
RC
Kim
Seong-Tae
ST
Lane
William S
WS
Kastan
Michael B
MB
D'Andrea
Alan D
AD
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
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