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Review
. 2012 Nov 1;40(20):9990-10004.
doi: 10.1093/nar/gks818. Epub 2012 Aug 31.

DNA repair endonuclease ERCC1-XPF as a novel therapeutic target to overcome chemoresistance in cancer therapy

Ewan M McNeil  1 , David W Melton
Affiliations
Review

DNA repair endonuclease ERCC1-XPF as a novel therapeutic target to overcome chemoresistance in cancer therapy

Ewan M McNeil et al. Nucleic Acids Res. .

Abstract

The ERCC1-XPF complex is a structure-specific endonuclease essential for the repair of DNA damage by the nucleotide excision repair pathway. It is also involved in other key cellular processes, including DNA interstrand crosslink (ICL) repair and DNA double-strand break (DSB) repair. New evidence has recently emerged, increasing our understanding of its requirement in these additional roles. In this review, we focus on the protein-protein and protein-DNA interactions made by the ERCC1 and XPF proteins and discuss how these coordinate ERCC1-XPF in its various roles. In a number of different cancers, high expression of ERCC1 has been linked to a poor response to platinum-based chemotherapy. We discuss prospects for the development of DNA repair inhibitors that target the activity, stability or protein interactions of the ERCC1-XPF complex as a novel therapeutic strategy to overcome chemoresistance.

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Figures

Figure 1.
Figure 1.
Domain architecture of ERCC1 and XPF proteins. The active site within the XPF nuclease domain is shown as a green box. Confirmed protein–protein interacting regions are mapped and identified with black text; undefined or unconfirmed protein–protein interactions are identified by grey text. Amino acid substitution mutations identified in XP or XF-E patients are also indicated. The same colour scheme shown here to identify the protein domains is used in all the figures. NLS, putative nuclear localization signal.
Figure 2.
Figure 2.
Interaction of ERCC1 and XPF through their HhH2 domains. (A) Heterodimer of the HhH2 domains of ERCC1 (red) and XPF (blue). (B) Expanded cartoon representation of the region boxed on XPF, identifying key interacting residues in the XPF pocket for ERCC1 Phe293. (C) Expanded cartoon representation of the region boxed on ERCC1, identifying key interacting residues in the ERCC1 pocket for XPF Phe905. Figure created using PyMOL v0.99 with the ERCC1–XPF HhH2 domain crystal structure (PDB code 2A1J) (58).
Figure 3.
Figure 3.
Proposed model for ERCC1–XPF interaction with the DNA substrate. (A) Showing the ERCC1 HhH2 and central domains (red) and XPF HhH2 and nuclease domains (blue). DNA-binding regions are shown in yellow; the XPF nuclease active site is shown in green; the nucleotide-binding pocket on the XPF HhH2 domain is shown in orange; the XPA-binding site on the ERCC1 central domain is coloured magenta. The ERCC1 N-terminal region (ERCC11–98) and the XPF domain linking regions (XPF666 and XPF825–847) are not shown as crystal structures are not available and there is insufficient sequence conservation for homology modelling. (B) Same view as in (A), but with the addition of the proposed position of the XPF helicase-like domain and omitting the DNA substrate. The RPA-binding site on the XPF helicase-like domain is shown in cyan. (C) As in (B), but with a 90° anti-clockwise rotation of the ERCC1–XPF complex. (D) As in (B), but with a 90° clockwise rotation of the ERCC1–XPF complex. Figure created in PyMOL v0.99 using the ERCC1–XPF HhH2 domain crystal structure (PDB code 2A1J) (58), the ERCC1 central domain crystal structure (PDB code 2A1I) (58) and PHYRE-generated homology models of the XPF endonuclease and helicase-like domains.
Figure 4.
Figure 4.
The nuclease domain of XPF. Cartoon representation of XPF identifying amino acids and their side chains. Residues Asp687, Glu690, Asp715 and Glu725 are implicated in metal binding (67). No metal ion has been shown. Figure created using PyMOL v0.99 with a homology model of XPF generated using the Protein Homology/analogY Recognition Engine v2.0 (PHYRE) (68).
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