Summary information and primary citation
- PDB-id
-
4reb;
DSSR-derived features in text and
JSON formats
- Class
- hydrolase-DNA
- Method
- X-ray (4.2 Å)
- Summary
- Structural insights into 5' flap DNA unwinding and
incision by the human fan1 dimer
- 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.
