title: Yeast Sub1 and human PC4 are G-quadruplex binding proteins that suppress genome instability at co-transcriptionally formed G4 DNA.
abstract: G-quadruplex or G4 DNA is a non-B secondary DNA structure consisting of a stacked array of guanine-quartets that can disrupt critical cellular functions such as replication and transcription. When sequences that can adopt Non-B structures including G4 DNA are located within actively transcribed genes, the reshaping of DNA topology necessary for transcription process stimulates secondary structure-formation thereby amplifying the potential for genome instability. Using a reporter assay designed to study G4-induced recombination in the context of an actively transcribed locus in Saccharomyces cerevisiae, we tested whether co-transcriptional activator Sub1, recently identified as a G4-binding factor, contributes to genome maintenance at G4-forming sequences. Our data indicate that, upon Sub1-disruption, genome instability linked to co-transcriptionally formed G4 DNA in Top1-deficient cells is significantly augmented and that its highly conserved DNA binding domain or the human homolog PC4 is sufficient to suppress G4-associated genome instability. We also show that Sub1 interacts specifically with co-transcriptionally formed G4 DNA in vivo and that yeast cells become highly sensitivity to G4-stabilizing chemical ligands by the loss of Sub1. Finally, we demonstrate the physical and genetic interaction of Sub1 with the G4-resolving helicase Pif1, suggesting a possible mechanism by which Sub1 suppresses instability at G4 DNA.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Lopez
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Shivani
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Shashank
authors.initials: S
authors.lastname: Hambarde
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Wezley C
authors.initials: WC
authors.lastname: Griffin
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Shubeena
authors.initials: S
authors.lastname: Chib
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Ira
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Raney
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Nayun
authors.initials: N
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000172:deficiency / Q000235:genetics; D004271:DNA, Fungal / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D054856:G-Quadruplexes; D015966:Gene Expression Regulation, Fungal; D016678:Genome; D042822:Genomic Instability; D006801:Humans; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004271:DNA, Fungal; D004268:DNA-Binding Proteins; C101206:SUB1 protein, S cerevisiae; C509201:SUB1 protein, human; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C085463:PIF1 protein, S cerevisiae; D004265:DNA Helicases; D004264:DNA Topoisomerases, Type I