Structural determinants of human FANCF protein that function in the assembly of a DNA damage signaling complex

Przemysław Kowal, Allan M. Gurtan, Patricia Stuckert, Alan D. D'Andrea, Tom Ellenberger

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Fanconi anemia (FA) is a rare autosomal recessive and X-linked chromosomal instability disorder. At least eight FA proteins (FANCA, B, C, E, F, G, L, and M) form a nuclear core complex required for monoubiquitination of a downstream protein, FANCD2. The human FANCF protein reportedly functions as a molecular adaptor within the FA nuclear complex, bridging between the subcomplexes A:G and C:E. Our x-ray crystallographic studies of the C-terminal domain of FANCF reveal a helical repeat structure similar to the Cand1 regulator of the Cul1-Rbx1-Skp1-FboxSkp2 ubiquitin ligase complex. Two C-terminal loops of FANCF are essential for monoubiquitination of FANCD2 and normal cellular resistance to the DNA cross-linking agent mitomycin C. FANCF mutants bearing amino acid substitutions in this C-terminal surface fail to interact with other components of the FA complex, indicating that this surface is critical for the proper assembly of the FA core complex.

Original languageEnglish
Pages (from-to)2047-2055
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number3
DOIs
StatePublished - Jan 19 2007

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