Translesion DNA synthesis across double-base lesions derived from cross-links of an antitumor trinuclear platinum compound: primer extension, conformational and thermodynamic studies

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F18%3A00502569" target="_blank" >RIV/68081707:_____/18:00502569 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1039/c7mt00266a" target="_blank" >http://dx.doi.org/10.1039/c7mt00266a</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/c7mt00266a" target="_blank" >10.1039/c7mt00266a</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Translesion DNA synthesis across double-base lesions derived from cross-links of an antitumor trinuclear platinum compound: primer extension, conformational and thermodynamic studies

Popis výsledku v původním jazyce

Polynuclear platinum complexes represent a unique structural class of DNA-binding agents of biological significance. They contain at least two platinum coordinating units bridged by a linker, which means that the formation of double-base lesions (cross-links) in DNA is possible. Here, we show that the lead compound, bifunctional [{trans-PtCl(NH3)(2)}(2)mu-trans-Pt(NH3)(2){H2N(CH2)(6)NH2}(2)](4+) (Triplatin or BBR3464), forms in DNA specific double-base lesions which affect the biophysical and biochemical properties of DNA in a way fundamentally different compared to the analogous double-base lesions formed by two adducts of monofunctional chlorodiethylenetriamineplatinum(II) chloride (dienPt). We find concomitantly that translesion DNA synthesis by the model A-family polymerase, the exonuclease deficient Klenow fragment, across the double-base lesions derived from the intrastrand CLs of Triplatin was markedly less extensive than that across the two analogous monofunctional adducts of dienPt. Collectively, these data provide convincing support for the hypothesis that the central noncovalent tetraamine platinum linker of Triplatin, capable of hydrogen-bonding and electrostatic interactions with DNA and bridging the two platinum adducts, represents an important factor responsible for the markedly lowered tolerance of DNA double-base adducts of Triplatin by DNA polymerases.

Název v anglickém jazyce

Translesion DNA synthesis across double-base lesions derived from cross-links of an antitumor trinuclear platinum compound: primer extension, conformational and thermodynamic studies

Popis výsledku anglicky

Polynuclear platinum complexes represent a unique structural class of DNA-binding agents of biological significance. They contain at least two platinum coordinating units bridged by a linker, which means that the formation of double-base lesions (cross-links) in DNA is possible. Here, we show that the lead compound, bifunctional [{trans-PtCl(NH3)(2)}(2)mu-trans-Pt(NH3)(2){H2N(CH2)(6)NH2}(2)](4+) (Triplatin or BBR3464), forms in DNA specific double-base lesions which affect the biophysical and biochemical properties of DNA in a way fundamentally different compared to the analogous double-base lesions formed by two adducts of monofunctional chlorodiethylenetriamineplatinum(II) chloride (dienPt). We find concomitantly that translesion DNA synthesis by the model A-family polymerase, the exonuclease deficient Klenow fragment, across the double-base lesions derived from the intrastrand CLs of Triplatin was markedly less extensive than that across the two analogous monofunctional adducts of dienPt. Collectively, these data provide convincing support for the hypothesis that the central noncovalent tetraamine platinum linker of Triplatin, capable of hydrogen-bonding and electrostatic interactions with DNA and bridging the two platinum adducts, represents an important factor responsible for the markedly lowered tolerance of DNA double-base adducts of Triplatin by DNA polymerases.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/GA17-09436S" target="_blank" >GA17-09436S: Translézová syntéza DNA přes léze vyvolané biologicky významnými agens z pohledu energetiky, kinetiky a mechanismu</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

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

Název periodika

Metallomics

ISSN

1756-5901

e-ISSN

—

Svazek periodika

10

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

13

Strana od-do

132-144

Kód UT WoS článku

000423352400010

EID výsledku v databázi Scopus

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