Dissection of the xeroderma pigmentosum group C protein function by site-directed mutagenesis

Antioxidants & Redox Signaling
Flurina C ClementHanspeter Naegeli

Abstract

Xeroderma pigmentosum group C (XPC) protein is a sensor of helix-distorting DNA lesions, the function of which is to trigger the global genome repair (GGR) pathway. Previous studies demonstrated that XPC protein operates by detecting the single-stranded character of non-hydrogen-bonded bases opposing lesion sites. This mode of action is supported by structural analyses of the yeast Rad4 homologue that identified critical side chains making close contacts with a pair of extrahelical nucleotides. Here, alanine substitutions of the respective conserved residues (N754, F756, F797, F799) in human XPC were tested for DNA-binding activity, accumulation in tracks and foci of DNA lesions, nuclear protein mobility, and the induction of downstream GGR reactions. This study discloses a dynamic interplay between XPC protein and DNA, whereby the association with one displaced nucleotide in the undamaged strand mediates the initial encounter with lesion sites. The additional flipping-out of an adjacent nucleotide is necessary to hand over the damaged site to the next GGR player. Surprisingly, this mutagenesis analysis also reveals that the rapid intranuclear trafficking of XPC protein depends on constitutive interactions with native DNA, impl...Continue Reading

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Citations

Jan 18, 2011·Antioxidants & Redox Signaling·Tracy M Neher, John J Turchi
Jan 29, 2014·Biophysical Chemistry·Caterina Bianchi, Ronen Zangi
Nov 2, 2015·Cellular and Molecular Life Sciences : CMLS·Marjo-Riitta PuumalainenHanspeter Naegeli
Mar 22, 2015·Mutation Research. Reviews in Mutation Research·Bruno César Feltes, Diego Bonatto
Jun 25, 2019·Physical Chemistry Chemical Physics : PCCP·Zhaoxi SunQiaole He

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Methods Mentioned

BETA
transfection
FCS
fluorescence recovery after photobleaching
fluorescence measurement after photobleaching
Assay
pull-down
transfecting

Software Mentioned

PyMol Molecular Viewer
InStat
GraphPad
ImageJ
LAS AF lite

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