Human XPG nuclease structure, assembly, and activities with insights for neurodegeneration and cancer from pathogenic mutations.

Proceedings of the National Academy of Sciences of the United States of America
Susan E TsutakawaJohn A Tainer

Abstract

Xeroderma pigmentosum group G (XPG) protein is both a functional partner in multiple DNA damage responses (DDR) and a pathway coordinator and structure-specific endonuclease in nucleotide excision repair (NER). Different mutations in the XPG gene ERCC5 lead to either of two distinct human diseases: Cancer-prone xeroderma pigmentosum (XP-G) or the fatal neurodevelopmental disorder Cockayne syndrome (XP-G/CS). To address the enigmatic structural mechanism for these differing disease phenotypes and for XPG's role in multiple DDRs, here we determined the crystal structure of human XPG catalytic domain (XPGcat), revealing XPG-specific features for its activities and regulation. Furthermore, XPG DNA binding elements conserved with FEN1 superfamily members enable insights on DNA interactions. Notably, all but one of the known pathogenic point mutations map to XPGcat, and both XP-G and XP-G/CS mutations destabilize XPG and reduce its cellular protein levels. Mapping the distinct mutation classes provides structure-based predictions for disease phenotypes: Residues mutated in XP-G are positioned to reduce local stability and NER activity, whereas residues mutated in XP-G/CS have implied long-range structural defects that would likely di...Continue Reading

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Citations

Jan 5, 2021·British Journal of Biomedical Science·L YuanL Zeng
Mar 7, 2021·Progress in Biophysics and Molecular Biology·My T NguyenStanton L Gerson
Sep 24, 2020·Progress in Biophysics and Molecular Biology·Michal HammelJohn A Tainer
Apr 29, 2021·Cancer Management and Research·WeiLing YuSha Xiao
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Sep 26, 2021·Proteins·Leila T AlexanderTorsten Schwede
Jan 26, 2022·Biochemical Society Transactions·Areetha D'SouzaWalter J Chazin

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Methods Mentioned

BETA
X-ray
electron microscopy
immunoprecipitation
size-exclusion chromatography
light scattering
transfection

Software Mentioned

XPGcat
Gatan Digital Image
ImageJ

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