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Inhibition of mammalian DNA polymerases by resveratrol: mechanism and structural determinants

Authors :
Locatelli, Giada A.
Savio, Monica
Forti, Luca
Shevelev, Igor
Ramadan, Kristijan
Stivala, Lucia A.
Vannini, Vanio
Hübscher, Ulrich
Spadari, Silvio
Maga, Giovanni
Source :
Biochemical Journal; July 2005, Vol. 389 Issue: 2 p259-268, 10p
Publication Year :
2005

Abstract

Resveratrol, a natural compound found in many dietary plants and in red wine, plays an important role in the prevention of many human pathological processes, including inflammation, atherosclerosis and carcinogenesis. We have shown that the antiproliferative activity of resveratrol correlated with its ability to inhibit the replicative pols (DNA polymerases) α and δ in vitro [Stivala, Savio, Carafoli, Perucca, Bianchi, Maga, Forti, Pagnoni, Albini, Prosperi and Vannini (2001) J. Biol. Chem. 276, 22586–22594]. In this paper, we present the first detailed biochemical investigation on the mechanism of action of resveratrol towards mammalian pols. Our results suggest that specific structural determinants of the resveratrol molecule are responsible for selective inhibition of different mammalian pols, such as the family B pol α and the family X pol λ. Moreover, the resveratrol derivative trans-3,5-dimethoxy-4-hydroxystilbene, which is endowed with a strong antiproliferative activity (Stivala et al., 2001), can inhibit pols α and λ and also suppress the in vitro SV40 DNA replication. The potency of inhibition is similar to that of aphidicolin, an inhibitor of the three replicative pols α, δ and ε. Our findings establish the necessary background for the synthesis of resveratrol derivatives having more selective and potent antiproliferative activity.

Details

Language :
English
ISSN :
02646021 and 14708728
Volume :
389
Issue :
2
Database :
Supplemental Index
Journal :
Biochemical Journal
Publication Type :
Periodical
Accession number :
ejs7408590
Full Text :
https://doi.org/10.1042/BJ20050094