Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway.
Publication Type:Journal Article
Source:Science, Volume 333, Issue 6040, p.312-6 (2011)
Keywords:Amino Acid Sequence, Animals, Binding Sites, Crystallography, X-Ray, DNA, DNA Repair, DNA, Single-Stranded, Fanconi Anemia, Fanconi Anemia Complementation Group D2 Protein, Fanconi Anemia Complementation Group Proteins, Hydrophobic and Hydrophilic Interactions, Mice, Models, Molecular, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein Conformation, Protein Folding, Protein Structure, Secondary, Protein Structure, Tertiary, Static Electricity, Ubiquitin, Ubiquitination
<p>Fanconi anemia is a cancer predisposition syndrome caused by defects in the repair of DNA interstrand cross-links (ICLs). Central to this pathway is the Fanconi anemia I-Fanconi anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage-induced phosphorylation and monoubiquitination. The 3.4 angstrom crystal structure of the ~300 kilodalton ID complex reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8 angstrom electron-density map of FANCI-DNA crystals and in vitro data show that each protein has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an ICL.</p>