4REB

Structural Insights into 5' Flap DNA Unwinding and Incision by the Human FAN1 Dimer

Summary for 4REB

• Entry DOI: 10.2210/pdb4reb/pdb
• Related: 4REA 4REC
• Descriptor: DNA (5'-D(P*GP*TP*GP*GP*CP*GP*AP*GP*C)-3'), DNA (5'-D(P*CP*GP*TP*GP*GP*CP*GP*AP*GP*CP*GP*CP*TP*CP*GP*CP*CP*AP*CP*G)-3'), DNA (5'-D(P*GP*CP*TP*CP*GP*CP*CP*AP*CP*G)-3'), ... (5 entities in total)
• Functional Keywords: hjc, tpr, sap, structure specific nuclease, fancid2, nucleus, hydrolase-dna complex, hydrolase/dna
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : Q9Y2M0
• Total number of polymer chains: 5
• Total formula weight: 159548.22

Authors

Zhao, Q.,Xue, X.,Longerich, S.,Sung, P.,Xiong, Y. (deposition date: 2014-09-22, release date: 2014-12-24, Last modification date: 2024-02-28)

Primary citation

Zhao, Q.,Xue, X.,Longerich, S.,Sung, P.,Xiong, Y.
Structural insights into 5' flap DNA unwinding and incision by the human FAN1 dimer.
Nat Commun, 5:5726-5726, 2014

PubMed 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.

PubMed: 25500724
DOI: 10.1038/ncomms6726

Experimental method

X-RAY DIFFRACTION (4.2 Å)