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Cryo-EM structures of the XPF-ERCC1 endonuclease reveal how DNA-junction engagement disrupts an auto-inhibited conformation

Jones, M. and Beuron, F. and Borg, A. and Nans, A. and Earl, C.P. and Briggs, D.C. and Snijders, A.P. and Bowles, M. and Morris, E.P. and Linch, M. and McDonald, Neil Q. (2020) Cryo-EM structures of the XPF-ERCC1 endonuclease reveal how DNA-junction engagement disrupts an auto-inhibited conformation. Nature Communications 11 , p. 1120. ISSN 2041-1723.

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Abstract

The structure-specific endonuclease XPF-ERCC1 participates in multiple DNA damage repair pathways including nucleotide excision repair (NER) and in¬ter-strand crosslink repair (ICLR). How XPF-ERCC1 is catalytically activated by DNA junction substrates is not currently understood. Here we report cryo-electron mi¬croscopy structures of both DNA-free and DNA-bound human XPF-ERCC1. DNA-free XPF-ERCC1 adopts an auto-inhibited conformation in which the XPF heli¬cal domain masks the ERCC1 (HhH)2 domain and restricts access to the XPF catalytic site. DNA junction engagement releases the ERCC1 (HhH)2 domain to couple with the XPF-ERCC1 nuclease/nuclease-like domains. Structure-function data indicate xeroderma pigmentosum patient mutations frequently compromise the structural integrity of XPF-ERCC1. Fanconi anaemia patient mutations often display sub¬stantial in-vitro activity but are resistant to activation by ICLR recruitment factor SLX4. Our data provide insights into XPF-ERCC1 architecture and catalytic activation.

Metadata

Item Type: Article
School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
Depositing User: Neil Mcdonald
Date Deposited: 02 Mar 2020 10:46
Last Modified: 11 Jun 2025 03:27
URI: https://eprints.bbk.ac.uk/id/eprint/28892

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