4bxo

Publication Abstract from PubMed

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.

Architecture and DNA Recognition Elements of the Fanconi Anemia FANCM-FAAP24 Complex.,Coulthard R, Deans AJ, Swuec P, Bowles M, Costa A, West SC, McDonald NQ Structure. 2013 Aug 6. pii: S0969-2126(13)00255-4. doi:, 10.1016/j.str.2013.07.006. PMID:23932590^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.