DNA three-way junctions are critical in various biological processes and hold significant potential for disease treatment and therapeutic applications. In this study, it is demonstrated that triple-stranded dinuclear [Ni2L3]4+ cylinders (L = C25H20N4) exhibit a preferential binding affinity for Y-shaped DNA three-way junctions (3WJs), even in the presence of an excess of competing DNA structures, including G-quadruplexes. Notably, the investigated Ni(II) cylinders are capable of halting DNA synthesis catalyzed by DNA polymerase by stabilizing the 3WJ on the template strand. Using an extended 1D nanoarchitecture model, it is further established the high affinity and selectivity of the cylinders for DNA 3WJs and explored their potential application in stabilizing short-armed 3WJs for constructing DNA nanomaterials. The combined use of Ni(II) cylinders and DNA damage response inhibitors also revealed that the cylinders promote DNA damage, leading to the formation of double-strand breaks. This effect is likely associated with i) the binding of cylinders to 3WJs and ii) the cytotoxic activity of the cylinders in cancer cells.

• Klíčová slova
• DNA damage, DNA nanomaterials, DNA three‐way junctions, Ni(II) cylinders, cytotoxicity,
• MeSH
• DNA * chemie   metabolismus   MeSH
• G-kvadruplexy MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   patologie   metabolismus   MeSH
• nikl * chemie   MeSH
• poškození DNA * MeSH
• replikace DNA účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA * MeSH
• nikl * MeSH

DNA three-way junctions (3WJ) represent one of the simplest supramolecular DNA structures arising as intermediates in homologous recombination in the absence of replication. They are also formed transiently during DNA replication. Here we examine the ability of Fe(II)-based metallohelices to act as DNA 3WJ binders and induce DNA damage in cells. We investigated the interaction of eight pairs of enantiomerically pure Fe(II) metallohelices with four different DNA junctions using biophysical and molecular biology methods. The results show that the metallohelices stabilize all types of tested DNA junctions, with the highest selectivity for the Y-shaped 3WJ and minimal selectivity for the 4WJ. The potential of the best stabilizer of DNA junctions and, at the same time, the most selective 3WJ binder investigated in this work to induce DNA damage was determined in human colon cancer HCT116 cells. These metallohelices proved to be efficient in killing cancer cells and triggering DNA damage that could yield therapeutic benefits.

• MeSH
• DNA * chemie   MeSH
• konformace nukleové kyseliny MeSH
• lidé MeSH
• nádory * genetika   MeSH
• poškození DNA MeSH
• železnaté sloučeniny MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA * MeSH
• železnaté sloučeniny MeSH

The interaction between the HIV-1 transactivator protein Tat and TAR (transactivation responsive region) RNA, plays a critical role in HIV-1 transcription. Iron(II) supramolecular helicates were evaluated for their in vitro activity to inhibit Tat-TAR RNA interaction using UV melting studies, electrophoretic mobility shift assay, and RNase A footprinting. The results demonstrate that iron(II) supramolecular helicates inhibit Tat-TAR interaction at nanomolar concentrations by binding to TAR RNA. These studies provide a new insight into the biological potential of metallosupramolecular helicates.

• MeSH
• genové produkty tat - virus lidské imunodeficience metabolismus   MeSH
• HIV-1 účinky léků   fyziologie   MeSH
• konformace nukleové kyseliny MeSH
• replikace viru účinky léků   MeSH
• RNA virová chemie   metabolismus   MeSH
• vazba proteinů MeSH
• železnaté sloučeniny chemie   farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• genové produkty tat - virus lidské imunodeficience MeSH
• RNA virová MeSH
• železnaté sloučeniny MeSH

[Fe(2)L(3)](4+) (L = C(25)H(20)N(4)) is a synthetic tetracationic supramolecular cylinder (with a triple helical architecture) that targets the major groove of DNA and can bind to DNA Y-shaped junctions. To explore the DNA-binding mode of [Fe(2)L(3)](4+), we examine herein the interactions of pure enantiomers of this cylinder with DNA by biochemical and molecular biology methods. The results have revealed that, in addition to the previously reported bending of DNA, the enantiomers extensively unwind DNA, with the M enantiomer being the more efficient at unwinding, and exhibit preferential binding to regular alternating purine-pyrimidine sequences, with the M enantiomer showing a greater preference. Also, interestingly, the DNA binding of bulky cylinders [Fe(2)(L-CF(3))(3)](4+) and [Fe(2)(L-Ph)(3)](4+) results in no DNA unwinding and also no sequence preference of their DNA binding was observed. The observation of sequence-preference in the binding of these supramolecular cylinders suggests that a concept based on the use of metallosupramolecular cylinders might result in molecular designs that recognize the genetic code in a sequence-dependent manner with a potential ability to affect the processing of the genetic code.

• MeSH
• deoxyribonukleasa I MeSH
• DNA footprinting MeSH
• DNA chemie   metabolismus   MeSH
• ethidium chemie   MeSH
• kompetitivní vazba MeSH
• konformace nukleové kyseliny MeSH
• pyridiny chemie   MeSH
• restrikční enzymy metabolismus   MeSH
• sekvence nukleotidů MeSH
• stereoizomerie MeSH
• superhelikální DNA chemie   MeSH
• železnaté sloučeniny chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• deoxyribonukleasa I MeSH
• DNA MeSH
• ethidium MeSH
• pyridiny MeSH
• restrikční enzymy MeSH
• superhelikální DNA MeSH
• železnaté sloučeniny MeSH