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Fanconi Anemia Complementation Group FANCD2 Protein Serine 331 Phosphorylation Is Important for Fanconi Anemia Pathway Function and BRCA2 Interaction

¹ Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia; Departments of ² Pediatrics, ³ Pathology, ⁴ Cell Biology, and ⁵ Laboratory Medicine, Yale University Medical School, New Haven, Connecticut; and ⁶ School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom

Requests for reprints: Gary M. Kupfer, Yale University, LMP 2074, Division of Peds Hem-Onc, 333 Cedar Street, New Haven, CT 06520. Phone: 203-785-4640; Fax: 203-737-2227; E-mail: gary.kupfer{at}yale.edu.

Fanconi anemia is a cancer-prone inherited bone marrow failure and cancer susceptibility syndrome with at least 13 complementation groups (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, and FANCN). Our laboratory has previously described several regulatory phosphorylation events for core complex member proteins FANCG and FANCA by phosphorylation. In this study, we report a novel phosphorylation site serine 331 (S331) of FANCD2, the pivotal downstream player of the Fanconi anemia pathway. Phosphorylation of S331 is important for its DNA damage–inducible monoubiquitylation, resistance to DNA cross-linkers, and in vivo interaction with FANCD1/BRCA2. A phosphomimetic mutation at S331 restores all of these phenotypes to wild-type. In vitro and in vivo experiments show that phosphorylation of S331 is mediated by CHK1, the S-phase checkpoint kinase implicated in the Fanconi anemia DNA repair pathway. [Cancer Res 2009;69(22):8775–83]

Key Words: phosphorylation • FANCD2 • genomic instability • BRCA2 • Fanconi anemia