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J. Biol. Chem., Vol. 279, Issue 44, 46035-46045, October 29, 2004

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Phosphorylation of Fanconi Anemia (FA) Complementation Group G Protein, FANCG, at Serine 7 Is Important for Function of the FA Pathway^*

Fengyu Qiao, Jun Mi, James B. Wilson¶||, Gang Zhi, Natalie R. Bucheimer, Nigel J. Jones¶, and Gary M. Kupfer, Supported by Grant HL-063776 from the NIHLB, National Institutes of Health**

From the Departments of Microbiology and ^**Pediatrics, University of Virginia Health System, Charlottesville, Virginia 22908 and the ^¶School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, United Kingdom

Fanconi anemia (FA) is an autosomal recessive disease of cancer susceptibility. FA cells exhibit a characteristic hypersensitivity to DNA cross-linking agents. The molecular mechanism for the disease is unknown as few of the FA proteins have functional motifs. Several post-translational modifications of the proteins have been described. We and others (Qiao, F., Moss, A., and Kupfer, G. M. (2001) J. Biol. Chem. 276, 23391–23396 and Futaki, M., Watanabe, S., Kajigaya, S., and Liu, J. M. (2001) Biochem. Biophys. Res. Commun. 281, 347–351) have reported that the FANCG protein (Fanconi complementation group G) is phosphorylated. We show that in an in vitro kinase reaction FANCG is radioactively labeled. Mass spectrometry analysis detected a peptide containing phosphorylation of serine 7. Using PCR-mediated site-directed mutagenesis we mutated serine 7 to alanine. Only wild-type FANCG cDNA fully corrected FA-G mutant cells. We also tested the effect of human wild-type FANCG in Chinese hamster ovary cells in which the FANCG homologue is mutant. Human FANCG complemented these cells, whereas human FANCG(S7A) did not. Unexpectedly, FANCG(S7A) bound to and stabilized the endogenous forms of the FANCA and FANCC proteins in the FA-G cells. FANCG(S7A) aberrantly localized to globules in chromatin and did not abrogate the internuclear bridges seen in the FA-G mutant cells. Phosphorylation of serine 7 in FANCG is functionally important in the FA pathway.

Received for publication, July 22, 2004 , and in revised form, August 2, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| Supported by a Grant from Northwest Cancer Research Fund (UK).

To whom correspondence should be addressed. E-mail: gk9{at}virginia.edu.

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