DNA repair gets physical: mapping an XPA-binding site on ERCC1

Abstract

Two recent reports provide new physical information on how the XPA protein recruits the ERCC1-XPF heterodimer to the site of damage during the process of mammalian nucleotide excision repair (NER). Using chemical shift perturbation NMR experiments, the contact sites between a central fragment of ERCC1 and an XPA fragment have been mapped. While both studies agree with regard to the XPA-binding site, they differ on whether the ERCC1-XPA complex can simultaneously bind DNA. These studies have important implications for both the molecular process and the design of potential inhibitors of NER.

Fig. 1. Model of Mammalian General Genome Repair

Mammalian NER proceeds through the sequential addition or exit of repair factors. See text for more details. The dashed red box in the penultimate step emphasizes the ERCC1-XPA interaction under investigation by Tripsianes et al. [1] and Tsodikov et al. [1,2].

Fig. 2. The domain organization of XPF, ERCC1 and XPA

The homology-based domains of human proteins are shown in different boxes with the boundary residue numbers. Known protein-protein interactions are denoted beneath the graphic representations.

Fig. 3. The structures of the nuclease domain of A. pernix XPF (PDB ID: 2BGW), the nuclease-like domain of human ERCC1 (PDB ID: 2JPD) and the C-terminal HhH₂ domain of human ERCC1-XPF complex (PDB ID: 2A1J)

(A) The crystal structure of the nuclease domain of A. pernix XPF. The important catalytic residues, Glu62, Arg63 and Lys64, are labeled green. (B) The NMR structure of the nuclease-like domain of human ERCC1. The non-catalytic residues in ERCC1's nuclease-like fold are Leu139, Leu141 and Phe140 and are noted in green. Those residues in black are proposed to interact with residues 67-80 in XPA (C) The crystal structure of the human C-terminal HhH₂ domain complex between the XPF and ERCC1. ERCC1 C-terminal domain is shown as green and XPF C-terminal domain as blue.