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Molecular and Cellular Biology, April 2007, p. 3098-3108, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.02357-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Chk1-Mediated Phosphorylation of FANCE Is Required for the Fanconi Anemia/BRCA Pathway{triangledown} ,{dagger}

XiaoZhe Wang,1 Richard D. Kennedy,1 Kallol Ray,1 Patricia Stuckert,1 Tom Ellenberger,2 and Alan D. D'Andrea1*

Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts,1 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri2

Received 18 December 2006/ Returned for modification 10 January 2007/ Accepted 30 January 2007

The eleven Fanconi anemia (FA) proteins cooperate in a novel pathway required for the repair of DNA cross-links. Eight of the FA proteins (A, B, C, E, F, G, L, and M) form a core enzyme complex, required for the monoubiquitination of FANCD2 and the assembly of FANCD2 nuclear foci. Here, we show that, in response to DNA damage, Chk1 directly phosphorylates the FANCE subunit of the FA core complex on two conserved sites (threonine 346 and serine 374). Phosphorylated FANCE assembles in nuclear foci and colocalizes with FANCD2. A nonphosphorylated mutant form of FANCE (FANCE-T346A/S374A), when expressed in a FANCE-deficient cell line, allows FANCD2 monoubiquitination, FANCD2 foci assembly, and normal S-phase progression. However, the mutant FANCE protein fails to complement the mitomycin C hypersensitivity of the transfected cells. Taken together, these results elucidate a novel role of Chk1 in the regulation of the FA/BRCA pathway and in DNA cross-link repair. Chk1-mediated phosphorylation of FANCE is required for a function independent of FANCD2 monoubiquitination.

* Corresponding author. Mailing address: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-2112. Fax: (617) 632-5757. E-mail: alan_dandrea{at}dfci.harvard.edu

{triangledown} Published ahead of print on 12 February 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2007, p. 3098-3108, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.02357-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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