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The crystal structure of human XPG, the xeroderma pigmentosum group G endonuclease, provides insight into nucleotide excision DNA repair

AuthorsGonzález-Corrochano, Rocío; Ruiz, Federico M. ; Taylor, Nicholas M. I.; Huecas, Sonia ; Drakulic, Srdja; Spínola-Amilibia, Mercedes ; Fernández-Tornero, Carlos
Issue Date21-Aug-2020
PublisherOxford University Press
CitationNucleic Acids Research gkaa688 (2020)
AbstractNucleotide excision repair (NER) is an essential pathway to remove bulky lesions affecting one strand of DNA. Defects in components of this repair system are at the ground of genetic diseases such as xeroderma pigmentosum (XP) and Cockayne syndrome (CS). The XP complementation group G (XPG) endonuclease cleaves the damaged DNA strand on the 3' side of the lesion coordinated with DNA re-synthesis. Here, we determined crystal structures of the XPG nuclease domain in the absence and presence of DNA. The overall fold exhibits similarities to other flap endonucleases but XPG harbors a dynamic helical arch that is uniquely oriented and defines a gateway. DNA binding through a helix-2-turn-helix motif, assisted by one flanking alpha-helix on each side, shows high plasticity, which is likely relevant for DNA scanning. A positively-charged canyon defined by the hydrophobic wedge and beta-pin motifs provides an additional DNA-binding surface. Mutational analysis identifies helical arch residues that play critical roles in XPG function. A model for XPG participation in NER is proposed. Our structures and biochemical data represent a valuable tool to understand the atomic ground of XP and CS, and constitute a starting point for potential therapeutic applications.
Description16 p.-7 fig.-1 tab.
Publisher version (URL)https://doi.org/10.1093/nar/gkaa688
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