Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M

Blood. 2009 Jul 2;114(1):174-80. doi: 10.1182/blood-2009-02-207811. Epub 2009 May 7.


FANCM is a component of the Fanconi anemia (FA) core complex and one FA patient (EUFA867) with biallelic mutations in FANCM has been described. Strikingly, we found that EUFA867 also carries biallelic mutations in FANCA. After correcting the FANCA defect in EUFA867 lymphoblasts, a "clean" FA-M cell line was generated. These cells were hypersensitive to mitomycin C, but unlike cells defective in other core complex members, FANCM(-/-) cells were proficient in monoubiquitinating FANCD2 and were sensitive to the topoisomerase inhibitor camptothecin, a feature shared only with the FA subtype D1 and N. In addition, FANCM(-/-) cells were sensitive to UV light. FANCM and a C-terminal deletion mutant rescued the cross-linker sensitivity of FANCM(-/-) cells, whereas a FANCM ATPase mutant did not. Because both mutants restored the formation of FANCD2 foci, we conclude that FANCM functions in an FA core complex-dependent and -independent manner.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Camptothecin / pharmacology
  • Cell Line, Tumor
  • Cross-Linking Reagents / pharmacology
  • DNA Helicases / deficiency
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism*
  • Drug Resistance / genetics
  • Drug Resistance / physiology
  • Fanconi Anemia / genetics*
  • Fanconi Anemia / metabolism*
  • Fanconi Anemia Complementation Group A Protein / genetics
  • Fanconi Anemia Complementation Group A Protein / metabolism
  • Fanconi Anemia Complementation Group D2 Protein / genetics*
  • Fanconi Anemia Complementation Group D2 Protein / metabolism*
  • Gene Expression
  • Humans
  • Mutation
  • Radiation Tolerance / genetics
  • Radiation Tolerance / physiology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Transfection
  • Ubiquitination / genetics
  • Ultraviolet Rays


  • Cross-Linking Reagents
  • FANCA protein, human
  • FANCD2 protein, human
  • Fanconi Anemia Complementation Group A Protein
  • Fanconi Anemia Complementation Group D2 Protein
  • Recombinant Proteins
  • Adenosine Triphosphatases
  • FANCM protein, human
  • DNA Helicases
  • Camptothecin