Nature Genetics
37, 958 - 963 (2005)
Published online: 21 August 2005; | doi:10.1038/ng1626
A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group MAmom Ruhikanta Meetei1, 2, Annette L Medhurst3, Chen Ling2, Yutong Xue2, Thiyam Ramsing Singh1, Patrick Bier3, Jurgen Steltenpool3, Stacie Stone4, Inderjeet Dokal5, Christopher G Mathew6, Maureen Hoatlin4, Hans Joenje3, Johan P de Winter3
& Weidong Wang21
Division of Experimental Hematology, Cincinnati Children's Hospital Research Foundation and University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA. 2
Laboratory of Genetics, National Institute on Aging, National Institutes of Health, 333 Cassell Drive, TRIAD Center Room 3000, Baltimore, Maryland 21224, USA. 3
Department of Clinical Genetics and Human Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. 4
Division of Molecular Medicine & Molecular and Medical Genetics/NRC3, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. 5
Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK. 6
Department of Medical and Molecular Genetics, Guy's, King's and St Thomas' School of Medicine, King's College London, London, UK.
Correspondence should be addressed to Johan P de Winter j.dewinter@vumc.nl or Weidong Wang wangw@grc.nia.nih.gov Fanconi anemia is a genetic disease characterized by genomic instability and cancer predisposition1. 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 proteins4,
5,
6. Each protein in this complex is essential for monoubiquitination of FANCD2, a key reaction in the Fanconi anemia DNA damage−response pathway2,
7. 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.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
