Transcription-facilitating histone chaperons interact with genomic and synthetic G4 structures

• Published in: International journal of biological macromolecules 2020-10, Vol.160, p.1144-1157
• Main Authors: Pavlova, Iulia I., Tsvetkov, Vladimir B., Isaakova, Ekaterina A., Severov, Vyacheslav V., Khomyakova, Ekaterina A., Lacis, Ivan A., Lazarev, Vassilii N., Lagarkova, Maria A., Pozmogova, Galina E., Varizhuk, Anna M.
• Format: Article
• Language: English
• Subjects: A549 Cells; Binding Sites; C-Myc; Cells, Cultured; DNA - chemistry; DNA - metabolism; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; G-Quadruplexes; Genes, myc; Hep G2 Cells; High Mobility Group Proteins - chemistry; High Mobility Group Proteins - metabolism; Histone Chaperones - chemistry; Histone Chaperones - metabolism; Histone chaperons; HT29 Cells; Humans; Molecular Docking Simulation; Nucleolin; Phosphoproteins - chemistry; Phosphoproteins - metabolism; Protein Binding; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - metabolism; Transcription Factors - chemistry; Transcription Factors - metabolism; Transcriptional Elongation Factors - chemistry; Transcriptional Elongation Factors - metabolism; X-linked Nuclear Protein - chemistry; X-linked Nuclear Protein - metabolism
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2020.05.173

Affinity for G-quadruplex (G4) structures may be a common feature of transcription-facilitating histone chaperons (HCs). This assumption is based on previous unmatched studies of HCs FACT, nucleolin (NCL), BRD3, and ATRX. We verified this assumption and considered its implications for the therapeutic applications of synthetic (exogenous) G4s and the biological significance of genomic G4s. First, we questioned whether exogenous G4s that recognize cell-surface NCL and could trap other HCs in the nucleus are usable as anticancer agents. We performed in vitro binding assays and selected leading multi-targeted G4s. They exhibited minor effects on cell viability. The presumed NCL-regulated intracellular transport of G4s was inefficient or insufficient for tumor-specific G4 delivery. Next, to clarify whether G4s in the human genome could recruit HCs, we compared available HC ChIP-seq data with G4-seq/G4-ChIP-seq data. Several G4s, including the well-known c-Myc quadruplex structure, were found to be colocalized with HC occupancy sites in cancer cell lines. As evidenced by our molecular modeling data, c-Myc G4 might interfere with the HC function of BRD3 but is unlikely to prevent the BRD3-driven assembly of the chromatin remodeling complex. The c-Myc case illustrates the intricate role of genomic G4s in chromatin remodeling, nucleosome remodeling, and transcription. [Display omitted]