TY - JOUR

T1 - Design and properties of ligand-conjugated guanine oligonucleotides for recovery of mutated G-quadruplexes

AU - Takahashi, Shuntaro

AU - Chelobanov, Boris

AU - Kim, Ki Tae

AU - Kim, Byeang Hyean

AU - Stetsenko, Dmitry

AU - Sugimoto, Naoki

N1 - Publisher Copyright: © 2018 by the authors.

PY - 2018/12/6

Y1 - 2018/12/6

N2 - The formation of a guanine quadruplex DNA structure (G4) is known to repress the expression of certain cancer-related genes. Consequently, a mutated G4 sequence can affect quadruplex formation and induce cancer progression. In this study, we developed an oligonucleotide derivative consisting of a ligand-containing guanine tract that replaces the mutated G4 guanine tract at the promoter of the vascular endothelial growth factor (VEGF) gene. A ligand moiety consisting of three types of polyaromatic hydrocarbons, pyrene, anthracene, and perylene, was attached to either the 30 or 50 end of the guanine tract. Each of the ligand-conjugated guanine tracts, with the exception of anthracene derivatives, combined with other intact guanine tracts to form an intermolecular G4 on the mutated VEGF promoter. This intermolecular G4, exhibiting parallel topology and high thermal stability, enabled VEGF G4 formation to be recovered from the mutated sequence. Stability of the intramolecular G4 increased with the size of the conjugated ligand. However, suppression of intermolecular G4 replication was uniquely dependent on whether the ligand was attached to the 30 or 50 end of the guanine tract. These results indicate that binding to either the top or bottom guanine quartet affects unfolding kinetics due to polarization in DNA polymerase processivity. Our findings provide a novel strategy for recovering G4 formation in case of damage, and fine-tuning processes such as replication and transcription.

AB - The formation of a guanine quadruplex DNA structure (G4) is known to repress the expression of certain cancer-related genes. Consequently, a mutated G4 sequence can affect quadruplex formation and induce cancer progression. In this study, we developed an oligonucleotide derivative consisting of a ligand-containing guanine tract that replaces the mutated G4 guanine tract at the promoter of the vascular endothelial growth factor (VEGF) gene. A ligand moiety consisting of three types of polyaromatic hydrocarbons, pyrene, anthracene, and perylene, was attached to either the 30 or 50 end of the guanine tract. Each of the ligand-conjugated guanine tracts, with the exception of anthracene derivatives, combined with other intact guanine tracts to form an intermolecular G4 on the mutated VEGF promoter. This intermolecular G4, exhibiting parallel topology and high thermal stability, enabled VEGF G4 formation to be recovered from the mutated sequence. Stability of the intramolecular G4 increased with the size of the conjugated ligand. However, suppression of intermolecular G4 replication was uniquely dependent on whether the ligand was attached to the 30 or 50 end of the guanine tract. These results indicate that binding to either the top or bottom guanine quartet affects unfolding kinetics due to polarization in DNA polymerase processivity. Our findings provide a novel strategy for recovering G4 formation in case of damage, and fine-tuning processes such as replication and transcription.

KW - Cancer

KW - G-quadruplex

KW - Ligand

KW - Replication

KW - replication

KW - MECHANISM

KW - OXIDATIVE DNA-DAMAGE

KW - cancer

KW - ligand

UR - http://www.scopus.com/inward/record.url?scp=85057712404&partnerID=8YFLogxK

U2 - 10.3390/molecules23123228

DO - 10.3390/molecules23123228

M3 - Article

C2 - 30563296

AN - SCOPUS:85057712404

VL - 23

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 12

M1 - 3228

ER -