title: G quadruplexes are genomewide targets of transcriptional helicases XPB and XPD.
abstract: G4 motifs are greatly enriched near promoters, suggesting that quadruplex structures may be targets of transcriptional regulation. Here we show, by ChIP-Seq analysis of human cells, that 40% of the binding sites of the transcription-associated helicases, XPB and XPD, overlap with G4 motifs. The highly significant overlap of XPB and XPD binding sites with G4 motifs cannot be explained by GC richness or parameters of the genomewide analysis, but instead suggests that these proteins are recruited to quadruplex structures that form in genomic DNA (G4 DNA). Biochemical analysis demonstrates that XPD is a robust G4 DNA helicase and that XPB binds G4 DNA. XPB and XPD are enriched near the transcription start site at 20% of genes, especially highly transcribed genes. XPB and XPD enrichment at G4 motifs characterizes specific signaling pathways and regulatory pathways associated with specific cancers. These results identify new candidate pathways for therapies targeted to quadruplexes.
authors.affiliation: Department of Immunology, University of Washington, Seattle, Washington, USA.
authors.forename: Lucas T
authors.initials: LT
authors.lastname: Gray
authors.affiliation: 1] Department of Immunology, University of Washington, Seattle, Washington, USA. [2].
authors.forename: Aarthy C
authors.initials: AC
authors.lastname: Vallur
authors.affiliation: 1] Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, USA. [2].
authors.forename: Johanna
authors.initials: J
authors.lastname: Eddy
authors.affiliation: 1] Department of Immunology, University of Washington, Seattle, Washington, USA. [2] Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, USA. [3] Department of Biochemistry, University of Washington, Seattle, Washington, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Maizels
mesh_terms: D053801:Capillary Electrochromatography; D002460:Cell Line; D004247:DNA / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D054856:G-Quadruplexes; D005786:Gene Expression Regulation / Q000235:genetics*; D005822:Genetic Vectors; D016678:Genome / Q000235:genetics*; D006801:Humans; D046228:Microarray Analysis; D017354:Point Mutation / Q000235:genetics / Q000502:physiology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C072022:XPBC-ERCC-3 protein; D012313:RNA; D004247:DNA; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human