4REA: A Nuclease Dna Complex

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.
PDB ID: 4READownload
MMDB ID: 126184
PDB Deposition Date: 2014/9/22
Updated in MMDB: 2016/05
Experimental Method:
x-ray diffraction
Resolution: 3.81  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 4REA: pentameric; determined by author
Molecular Components in 4REA
Label Count Molecule
Proteins (2 molecules)
Fanconi-associated Nuclease 1(Gene symbol: FAN1)
Molecule annotation
Nucleotides(3 molecules)
DNA (5'-d(*tp*gp*cp*tp*cp*gp*cp*cp*ap*c)-3')
Molecule annotation
DNA (5'-d(p*cp*gp*tp*gp*gp*cp*gp*ap*gp*c)-3')
Molecule annotation
DNA (5'- D(p*gp*gp*cp*gp*ap*gp*cp*gp*cp*tp*cp*gp*cp*cp*ap*cp*g)-3')
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB