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 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.

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Figure 1: FAAP250 is an integral component of the Fanconi anemia core complex.
Figure 2: FAAP250 is required for FANCD2 monoubiquitination and is hyperphosphorylated in response to DNA damage.
Figure 3: FANCM (FAAP250) contains potential DNA-metabolizing domains and is homologous to DNA repair proteins in archaea and yeast.
Figure 4: FAAP250 has an ATP-dependent DNA translocase activity.
Figure 5: FANCM is mutated in individuals with Fanconi anemia and is essential for Fanconi anemia core complex assembly and function.

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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.

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Correspondence to Johan P de Winter or Weidong Wang.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

HeLa cells depleted of FAAP250 and FA-M patient cell line deficient of FAAP250 show increased sensitivity to mitomycin C (MMC). (PDF 6 kb)

Supplementary Fig. 2

FANCM (FAAP250) contains a highly-conserved helicase domain. (PDF 352 kb)

Supplementary Fig. 3

The endonuclease domains of the FANCM family of proteins are degenerate at several residues that are conserved in ERCC4/XPF and Hef proteins. (PDF 331 kb)

Supplementary Fig. 4

FANCM shows no detectable helicase activity for several DNA substrates and in the presence of replication protein A (RPA). (PDF 791 kb)

Supplementary Fig. 5

Identification of the FANCM deletion in EUFA867 patient. (PDF 50 kb)

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Meetei, A., Medhurst, A., Ling, C. et al. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet 37, 958–963 (2005). https://doi.org/10.1038/ng1626

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