Репозиторий Университета

© 2020 Elsevier B.V. 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.

© 2019, © 2019 Informa UK Limited, trading as Taylor  &  Francis Group. Human polymorphonuclear leukocytes (PMNLs, neutrophils) play a major role in the immune response to bacterial and fungal infections and eliminate pathogens through phagocytosis. During phagocytosis of microorganisms, the 5-lipoxygenase (5-LOX) pathway is activated resulting in generation of leukotrienes, which mediate host defense. In this study, a library of oligodeoxyribonucleotides (ODNs) with varying numbers of human telomeric repeats (d(TTAGGG)n) and their analogues with phosphorothioate internucleotide linkages and single-nucleotide substitutions was designed. These ODNs with the potential to fold into G-quadruplex structures were studied from structural and functional perspectives. We showed that exogenous G-quadruplex-forming ODNs significantly enhanced 5-LOX metabolite formation in human neutrophils exposed to Salmonella Typhimurium bacteria. However, the activation of leukotriene synthesis was completely lost when G-quadruplex formation was prevented by substitution of guanosine with 7-deazaguanosine or adenosine residues at several positions. To our knowledge, this study is the first to demonstrate that G-quadruplex structures are potent regulators of 5-LOX product synthesis in human neutrophils in the presence of targets of phagocytosis. Communicated by Ramaswamy H. Sarma.