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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Ataxia Telangiectasia / genetics
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Ataxia Telangiectasia / metabolism*
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Ataxia Telangiectasia / physiopathology
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins
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Cell Line, Transformed
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cell Nucleus / radiation effects
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DNA-Binding Proteins
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Fanconi Anemia / genetics
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Fanconi Anemia / metabolism*
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Fanconi Anemia / physiopathology
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Fanconi Anemia Complementation Group D2 Protein
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G1 Phase / drug effects
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G1 Phase / radiation effects
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G2 Phase / drug effects
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G2 Phase / radiation effects
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Genes, cdc / drug effects
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Genes, cdc / radiation effects
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HeLa Cells
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Humans
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Mitomycin / pharmacology
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Mutation / drug effects
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Mutation / radiation effects
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Nuclear Proteins / deficiency*
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Nuclear Proteins / genetics
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Nucleic Acid Synthesis Inhibitors / pharmacology
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Phosphorylation / radiation effects
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Phosphoserine / antagonists & inhibitors
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Phosphoserine / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Radiation, Ionizing
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S Phase / drug effects
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S Phase / genetics
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S Phase / radiation effects
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Signal Transduction / drug effects
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Signal Transduction / genetics*
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Signal Transduction / radiation effects
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Tumor Suppressor Proteins
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Ubiquitin / genetics
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Ubiquitin / metabolism
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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FANCD2 protein, human
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Fanconi Anemia Complementation Group D2 Protein
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Nuclear Proteins
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Nucleic Acid Synthesis Inhibitors
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Tumor Suppressor Proteins
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Ubiquitin
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Phosphoserine
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Mitomycin
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases