Yeast Sub1 and human PC4 are G-quadruplex binding proteins that suppress genome instability at co-transcriptionally formed G4 DNA

• Christopher R. Lopez ^[1] ; Shivani Singh ^[1] ; Shashank Hambarde ^[1] ; Wezley C. Griffin ^[2] ; Jun Gao ^[2] ; Shubeena Chib ^[2] ; Yang Yu ^[3] ; Grzegorz Ira ^[3] ; Kevin D. Raney ^[2] ; Nayun Kim ^[1]
  1. [1] University of Texas Health Science Center at Houston

     University of Texas Health Science Center at Houston

     Estados Unidos

     
  2. [2] University of Arkansas for Medical Sciences

     University of Arkansas for Medical Sciences

     Township of Big Rock, Estados Unidos

     
  3. [3] Baylor College of Medicine

     Baylor College of Medicine

     Estados Unidos

     

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• Localización: Nucleic acids research, ISSN 0305-1048, Vol. 45, Nº. 10, 2017, págs. 5850-5862
• Idioma: inglés
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• Resumen

  • 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.