Oct 7, 2019

Cryo-EM Structures of the XPF-ERCC1 Endonuclease Reveal an Auto-Inhibited Conformation and the Basis for Activation

BioRxiv : the Preprint Server for Biology
Morgan L JonesNeil Q McDonald

Abstract

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.

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Mentioned in this Paper

Fanconi Anemia
ERCC1 protein, human
SLX4
DNA Repair
ERCC4 protein, human
Surgical Incisions
SLX4 protein, human
Excision
Enzyme Activity
Nucleotide Excision Repair

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