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Synthesis and Polymerase-Mediated Bypass Studies of the N2-deoxyguanosine DNA Damage Caused by a Lucidin Analogue

Synthesis and Polymerase-Mediated Bypass Studies of the N2-deoxyguanosine DNA Damage Caused by a Lucidin Analogue

Pratibha P Ghodke, S Harikrishna, P I Pradeepkumar

J Org Chem. 2015 Feb 20;80(4):2128-38.

PMID: 25574682

Abstract:

Lucidin is a genotoxic and mutagenic hydroxyanthraquinone metabolite, which originates from the roots of Rubia tinctorum L. (madder root). It reacts with exocyclic amino groups of DNA nucleobases and forms adducts/lesions leading to carcinogenesis. To study the effect of lucidin-induced DNA damage, herein, we report the first synthesis of a structural analogue of lucidin [N(2)-methyl-(1,3-dimethoxyanthraquinone)-deoxyguanosine, LdG] embedded DNAs utilizing phosphoramidite strategy. LdG modification in a DNA duplex imparts destabilization (ΔTm ∼5 °C/modification), which is attributed to the unfavorable contribution from the enthalpy. Primer extension studies using the Klenow fragment (exo(-)) of Escherichia coli DNA polymerase I demonstrate that bypass of LdG modification is error prone as well as slow compared to that across the unmodified sites. Molecular dynamics simulations of the binary complex of Bacillus fragment polymerase (homologue of the Klenow fragment) and LdG-DNA duplex elucidate the structural fluctuations imparted by the LdG lesion, as well as the molecular mechanism of bypass at the lesion site. Overall, the results presented here show that the lucidin adduct destabilizes DNA structure and reduces fidelity and processivity of DNA synthesis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP478080	Lucidin		478-08-0	Price

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