Architecture of the human XPC DNA repair and stem cell coactivator complex

The Xeroderma pigmentosum complementation group C (XPC) complex is a versatile factor involved in both nucleotide excision repair and transcriptional coactivation as a critical component of theNANOG, OCT4,andSOX2pluripotency gene regulatory network. Here we present the structure of the human holo-XP...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2015-12, Vol.112 (48), p.14817-14822
Main Authors: Zhang, Elisa T., He, Yuan, Grob, Patricia, Fong, Yick W., Nogales, Eva, Tjian, Robert
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
DNA Repair
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Electrons
Homeodomain Proteins - chemistry
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Microscopy
Multiprotein Complexes - chemistry
Multiprotein Complexes - genetics
Multiprotein Complexes - metabolism
Nanog Homeobox Protein
Octamer Transcription Factor-3 - chemistry
Octamer Transcription Factor-3 - genetics
Octamer Transcription Factor-3 - metabolism
Phylogenetics
Protein Structure, Quaternary
Protein Structure, Tertiary
SOXB1 Transcription Factors - chemistry
SOXB1 Transcription Factors - genetics
SOXB1 Transcription Factors - metabolism
Stem cells
Structure-Activity Relationship
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Summary:The Xeroderma pigmentosum complementation group C (XPC) complex is a versatile factor involved in both nucleotide excision repair and transcriptional coactivation as a critical component of theNANOG, OCT4,andSOX2pluripotency gene regulatory network. Here we present the structure of the human holo-XPC complex determined by single-particle electron microscopy to reveal a flexible, ear-shaped structure that undergoes localized loss of order upon DNA binding. We also determined the structure of the complete yeast homolog Rad4 holo-complex to find a similar overall architecture to the human complex, consistent with their shared DNA repair functions. Localized differences between these structures reflect an intriguing phylogenetic divergence in transcriptional capabilities that we present here. Having positioned the constituent subunits by tagging and deletion, we propose a model of key interaction interfaces that reveals the structural basis for this difference in functional conservation. Together, our findings establish a framework for understanding the structure-function relationships of the XPC complex in the interplay between transcription and DNA repair.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1520104112