Architecture and DNA recognition elements of the Fanconi anemia FANCM-FAAP24 complex.

Fanconi anemia (FA) is a disorder associated with a failure in DNA repair. FANCM (defective in FA complementation group M) and its partner FAAP24 target other FA proteins to sites of DNA damage. FANCM-FAAP24 is related to XPF/MUS81 endonucleases but lacks endonucleolytic activity. We report a structure of an FANCM ...
C-terminal fragment (FANCMCTD) bound to FAAP24 and DNA. This S-shaped structure reveals the FANCM (HhH)2 domain is buried, whereas the FAAP24 (HhH)2 domain engages DNA. We identify a second DNA contact and a metal center within the FANCM pseudo-nuclease domain and demonstrate that mutations in either region impair double-stranded DNA binding in vitro and FANCM-FAAP24 function in vivo. We show the FANCM translocase domain lies in proximity to FANCMCTD by electron microscopy and that binding fork DNA structures stimulate its ATPase activity. This suggests a tracking model for FANCM-FAAP24 until an encounter with a stalled replication fork triggers ATPase-mediated fork remodeling.
Mesh Terms:
Adenosine Triphosphate, Catalytic Domain, Cell Survival, Coordination Complexes, Cryoelectron Microscopy, Crystallography, X-Ray, DNA Damage, DNA Helicases, DNA Repair, DNA-Binding Proteins, Gene Knockdown Techniques, HEK293 Cells, Humans, Hydrolysis, Mitomycin, Models, Molecular, Mutagens, Nucleic Acid Conformation, Oligonucleotides, Protein Binding, Protein Structure, Secondary, RNA, Small Interfering
Structure
Date: Sep. 03, 2013
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