RT Journal Article
SR Electronic
T1 Cryo-EM Structures of the XPF-ERCC1 Endonuclease Reveal an Auto-Inhibited Conformation and the Basis for Activation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 796524
DO 10.1101/796524
A1 Morgan Jones
A1 Fabienne Beuron
A1 Aaron Borg
A1 Andrea Nans
A1 Christopher Earl
A1 David C. Briggs
A1 Maureen Bowles
A1 Edward P. Morris
A1 Mark Linch
A1 Neil Q. McDonald
YR 2019
UL http://biorxiv.org/content/early/2019/10/07/796524.abstract
AB The structure-specific endonuclease XPF-ERCC1 participates in multiple DNA damage repair pathways including nucleotide excision repair (NER) and inter-strand crosslink repair (ICLR). How XPF-ERCC1 is catalytically activated by DNA junction substrates is not currently understood. We report cryo-electron microscopy structures of both DNA-free and DNA-bound human XPF-ERCC1. DNA-free XPF-ERCC1 adopts an auto-inhibited conformation in which the XPF helical domain masks ERCC1 DNA-binding elements and restricts access to the XPF catalytic site. Binding of a model DNA junction separates the XPF helical and ERCC1 (HhH)2 domains, promoting activation. Using these structural data, we propose a model for a 5’-NER incision complex involving XPF-ERCC1-XPA and a DNA junction substrate. Structure-function data suggest xeroderma pigmentosum patient mutations often compromise the structural integrity of XPF-ERCC1. Fanconi anaemia patient mutations often display substantial in-vitro activity but are resistant to activation by ICLR recruitment factor SLX4. Our data provide insights into XPF-ERCC1 architecture and catalytic activation.