title: A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.
abstract: 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.
authors.affiliation: Division of Experimental Hematology, Cincinnati Children's Hospital Research Foundation and University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Amom Ruhikanta
authors.initials: AR
authors.lastname: Meetei
authors.forename: Annette L
authors.initials: AL
authors.lastname: Medhurst
authors.forename: Chen
authors.initials: C
authors.lastname: Ling
authors.forename: Yutong
authors.initials: Y
authors.lastname: Xue
authors.forename: Thiyam Ramsing
authors.initials: TR
authors.lastname: Singh
authors.forename: Patrick
authors.initials: P
authors.lastname: Bier
authors.forename: Jurgen
authors.initials: J
authors.lastname: Steltenpool
authors.forename: Stacie
authors.initials: S
authors.lastname: Stone
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
authors.forename: Maureen
authors.initials: M
authors.lastname: Hoatlin
authors.forename: Hans
authors.initials: H
authors.lastname: Joenje
authors.forename: Johan P
authors.initials: JP
authors.lastname: de Winter
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
mesh_terms: D001105:Archaea / Q000737:chemistry*; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D005075:Biological Evolution; D004247:DNA / Q000378:metabolism; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D005199:Fanconi Anemia / Q000201:enzymology / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein; D052240:Fanconi Anemia Complementation Group L Protein; D006389:Hemagglutinins, Viral / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D008025:Ligases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D025801:Ubiquitin / Q000378:metabolism; D014760:Viral Fusion Proteins / Q000172:deficiency / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D006389:Hemagglutinins, Viral; D009687:Nuclear Proteins; D025801:Ubiquitin; D014760:Viral Fusion Proteins; C060814:hemagglutinin esterase; D004247:DNA; C499908:FANCL protein, human; D052240:Fanconi Anemia Complementation Group L Protein; C518295:FANCM protein, human; D004265:DNA Helicases; D008025:Ligases