Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways

Cell. 2002 May 17;109(4):459-72. doi: 10.1016/s0092-8674(02)00747-x.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Ataxia Telangiectasia / genetics
  • Ataxia Telangiectasia / metabolism*
  • Ataxia Telangiectasia / physiopathology
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins
  • Cell Line, Transformed
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Nucleus / radiation effects
  • DNA-Binding Proteins
  • Fanconi Anemia / genetics
  • Fanconi Anemia / metabolism*
  • Fanconi Anemia / physiopathology
  • Fanconi Anemia Complementation Group D2 Protein
  • G1 Phase / drug effects
  • G1 Phase / radiation effects
  • G2 Phase / drug effects
  • G2 Phase / radiation effects
  • Genes, cdc / drug effects
  • Genes, cdc / radiation effects
  • HeLa Cells
  • Humans
  • Mitomycin / pharmacology
  • Mutation / drug effects
  • Mutation / radiation effects
  • Nuclear Proteins / deficiency*
  • Nuclear Proteins / genetics
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Phosphorylation / radiation effects
  • Phosphoserine / antagonists & inhibitors
  • Phosphoserine / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Radiation, Ionizing
  • S Phase / drug effects
  • S Phase / genetics
  • S Phase / radiation effects
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Signal Transduction / radiation effects
  • Tumor Suppressor Proteins
  • Ubiquitin / genetics
  • Ubiquitin / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • FANCD2 protein, human
  • Fanconi Anemia Complementation Group D2 Protein
  • Nuclear Proteins
  • Nucleic Acid Synthesis Inhibitors
  • Tumor Suppressor Proteins
  • Ubiquitin
  • Phosphoserine
  • Mitomycin
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases