title: Architecture of the human XPC DNA repair and stem cell coactivator complex.
abstract: 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 the NANOG, OCT4, and SOX2 pluripotency 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.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720; Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720; Li Ka Shing Center for Biomedical and Health Sciences, CIRM Center of Excellence, University of California Berkeley, CA 94720;
authors.forename: Elisa T
authors.identifier: http://orcid.org/0000-0003-1294-2372
authors.initials: ET
authors.lastname: Zhang
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94710;
authors.forename: Yuan
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720; Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720;
authors.forename: Patricia
authors.initials: P
authors.lastname: Grob
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720; Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720;
authors.forename: Yick W
authors.initials: YW
authors.lastname: Fong
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720; Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94710;
authors.forename: Eva
authors.initials: E
authors.lastname: Nogales
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720; Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720; Li Ka Shing Center for Biomedical and Health Sciences, CIRM Center of Excellence, University of California Berkeley, CA 94720; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789 jmlim@berkeley.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Tjian
mesh_terms: D000818:Animals; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D055748:SOXB1 Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D046912:Multiprotein Complexes; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C086984:XPC protein, human
keywords: DNA repair; biochemistry; stem cells; structure; transcription