Summary information and primary citation
- PDB-id
- 4rec; SNAP-derived features in text and JSON formats;
DNAproDB
- Class
- hydrolase-DNA
- Method
- X-ray (2.2 Å)
- Summary
- A nuclease-DNA complex form 3
- Reference
- Zhao Q, Xue X, Longerich S, Sung P, Xiong Y (2014): "Structural insights into 5' flap DNA unwinding and incision by the human FAN1 dimer." Nat Commun, 5, 5726. doi: 10.1038/ncomms6726.
- Abstract
- Human FANCD2-associated nuclease 1 (FAN1) is a DNA structure-specific nuclease involved in the processing of DNA interstrand crosslinks (ICLs). FAN1 maintains genomic stability and prevents tissue decline in multiple organs, yet it confers ICL-induced anti-cancer drug resistance in several cancer subtypes. Here we report three crystal structures of human FAN1 in complex with a 5' flap DNA substrate, showing that two FAN1 molecules form a head-to-tail dimer to locate the lesion, orient the DNA and unwind a 5' flap for subsequent incision. Biochemical experiments further validate our model for FAN1 action, as structure-informed mutations that disrupt protein dimerization, substrate orientation or flap unwinding impair the structure-specific nuclease activity. Our work elucidates essential aspects of FAN1-DNA lesion recognition and a unique mechanism of incision. These structural insights shed light on the cellular mechanisms underlying organ degeneration protection and cancer drug resistance mediated by FAN1.
