Dinuclear nickel(ii) supramolecular helicates down-regulate gene expression in human cells by stabilizing DNA G-quadruplexes formed in the promoter regions

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F22%3A00563243" target="_blank" >RIV/68081707:_____/22:00563243 - isvavai.cz</a>

Výsledek na webu

<a href="https://pubs.rsc.org/en/content/articlelanding/2022/QI/D2QI01435A" target="_blank" >https://pubs.rsc.org/en/content/articlelanding/2022/QI/D2QI01435A</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/d2qi01435a" target="_blank" >10.1039/d2qi01435a</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Dinuclear nickel(ii) supramolecular helicates down-regulate gene expression in human cells by stabilizing DNA G-quadruplexes formed in the promoter regions

Popis výsledku v původním jazyce

We investigated the interaction of the M- and P-enantiomers of the dinuclear nickel(ii) tetracationic supramolecular helicate ([Ni2L3](4+), L = C25H20N4) with a series of four DNA G-quadruplexes (G4s) (hTelo, c-myc, c-kit1, c-kit2) formed by the human telomeric sequence (hTelo) and in the promoter regions of c-MYC and c-KIT oncogenes. Utilizing a multi-platform approach based on biochemical and molecular biophysics methods to study these interactions, we show that [Ni2L3](4+) helicates preferably bind to G4s over duplex DNA and that their binding selectivities towards DNA G4 structures are comparable to those of renowned G4 binders. Additionally, primer extension studies on DNA templates containing G4-forming sequences proved that stabilization of hTelo and particularly c-myc G4s by the nickel(ii) helicates was sufficient to cause premature termination of DNA synthesis catalyzed by Taq DNA polymerase. We also confirmed that nickel helicates are taken up by human embryonic kidney (HEK 293) cells and enter the nucleus, where they bind to DNA. Results from qRT-PCR and western blotting demonstrated that [Ni2L3](4+) helicates downregulate c-MYC expression at mRNA and protein levels in HEK 293 cells in a dose-dependent manner.

Název v anglickém jazyce

Dinuclear nickel(ii) supramolecular helicates down-regulate gene expression in human cells by stabilizing DNA G-quadruplexes formed in the promoter regions

Popis výsledku anglicky

We investigated the interaction of the M- and P-enantiomers of the dinuclear nickel(ii) tetracationic supramolecular helicate ([Ni2L3](4+), L = C25H20N4) with a series of four DNA G-quadruplexes (G4s) (hTelo, c-myc, c-kit1, c-kit2) formed by the human telomeric sequence (hTelo) and in the promoter regions of c-MYC and c-KIT oncogenes. Utilizing a multi-platform approach based on biochemical and molecular biophysics methods to study these interactions, we show that [Ni2L3](4+) helicates preferably bind to G4s over duplex DNA and that their binding selectivities towards DNA G4 structures are comparable to those of renowned G4 binders. Additionally, primer extension studies on DNA templates containing G4-forming sequences proved that stabilization of hTelo and particularly c-myc G4s by the nickel(ii) helicates was sufficient to cause premature termination of DNA synthesis catalyzed by Taq DNA polymerase. We also confirmed that nickel helicates are taken up by human embryonic kidney (HEK 293) cells and enter the nucleus, where they bind to DNA. Results from qRT-PCR and western blotting demonstrated that [Ni2L3](4+) helicates downregulate c-MYC expression at mRNA and protein levels in HEK 293 cells in a dose-dependent manner.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/GA20-00735S" target="_blank" >GA20-00735S: Využití kovových supramolekulárních helikátů pro kondenzaci a transport DNA</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Inorganic Chemistry Frontiers

ISSN

2052-1553

e-ISSN

2052-1553

Svazek periodika

9

Číslo periodika v rámci svazku

21

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

10

Strana od-do

5597-5606

Kód UT WoS článku

000853772100001

EID výsledku v databázi Scopus

2-s2.0-85139428545