TY - JOUR
T1 - A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M
AU - Meetei, Amom Ruhikanta
AU - Medhurst, Annette L.
AU - Ling, Chen
AU - Xue, Yutong
AU - Singh, Thiyam Ramsing
AU - Bier, Patrick
AU - Steltenpool, Jurgen
AU - Stone, Stacie
AU - Dokal, Inderjeet
AU - Mathew, Christopher G.
AU - Hoatlin, Maureen
AU - Joenje, Hans
AU - De Winter, Johan P.
AU - Wang, Weidong
N1 - Funding Information:
We thank the individuals with Fanconi anemia and their families for contributing to this study, N. Sherman for mass spectrometry analysis, S. Brill for providing Mus81, R. Wood for XPF, R. Brosh and M. Kenny for RPA, R. Pattni for genotyping, M. Rooimans for technical assistance, the National Cell Culture Center for providing cells and D. Schlessinger for critical reading of the manuscript. Financial support was from the Fanconi anemia Research Fund, Ellison Medical Foundation (W.W.), the US National Institutes of Health (M.H.), Daniel Ayling Fanconi Anaemia Trust (C.G.M.) and the intramural program of National Institute of Health, National Institute on Aging (W.W.). J.P.d.W. and A.L.M. are supported by the Dutch Cancer Society and the Netherlands Organization for Health Research and Development.
PY - 2005/9
Y1 - 2005/9
N2 - Fanconi anemia is a genetic disease characterized by genomic instability and cancer predisposition 1. 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 proteins4-6. 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.
AB - Fanconi anemia is a genetic disease characterized by genomic instability and cancer predisposition 1. 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 proteins4-6. 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.
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U2 - 10.1038/ng1626
DO - 10.1038/ng1626
M3 - Article
C2 - 16116422
AN - SCOPUS:25144449181
SN - 1061-4036
VL - 37
SP - 958
EP - 963
JO - Nature genetics
JF - Nature genetics
IS - 9
ER -