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A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.

Fanconi anemia is a genetic disease characterized by genomic instability and cancer predisposition. Nine genes involved in Fanconi anemia have been identified; their products participate in a DNA damage-response network involving BRCA1 and BRCA2 (refs. 2,3). We previously purified a Fanconi anemia core complex containing the FANCL ubiquitin ligase and six other Fanconi anemia-associated proteins. Each protein in this complex is essential for monoubiquitination of FANCD2, a key reaction in the Fanconi anemia DNA damage-response pathway. Here we show that another component of this complex, FAAP250, is mutant in individuals with Fanconi anemia of a new complementation group (FA-M). FAAP250 or FANCM has sequence similarity to known DNA-repair proteins, including archaeal Hef, yeast MPH1 and human ERCC4 or XPF. FANCM can dissociate DNA triplex, possibly owing to its ability to translocate on duplex DNA. FANCM is essential for monoubiquitination of FANCD2 and becomes hyperphosphorylated in response to DNA damage. Our data suggest an evolutionary link between Fanconi anemia-associated proteins and DNA repair; FANCM may act as an engine that translocates the Fanconi anemia core complex along DNA.

Pubmed ID: 16116422


  • Meetei AR
  • Medhurst AL
  • Ling C
  • Xue Y
  • Singh TR
  • Bier P
  • Steltenpool J
  • Stone S
  • Dokal I
  • Mathew CG
  • Hoatlin M
  • Joenje H
  • de Winter JP
  • Wang W


Nature genetics

Publication Data

September 31, 2005

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA112775
  • Agency: Intramural NIH HHS, Id:

Mesh Terms

  • Archaea
  • BRCA1 Protein
  • BRCA2 Protein
  • Biological Evolution
  • DNA
  • DNA Helicases
  • DNA Repair
  • Fanconi Anemia
  • Fanconi Anemia Complementation Group D2 Protein
  • Fanconi Anemia Complementation Group L Protein
  • Hemagglutinins, Viral
  • Humans
  • Immunoprecipitation
  • Ligases
  • Molecular Sequence Data
  • Mutation
  • Nuclear Proteins
  • Phosphorylation
  • Protein Transport
  • Ubiquitin
  • Viral Fusion Proteins