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
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
PubMed ID: 23932590
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