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Synthesis and Polymerase-Mediated Bypass Studies of the N-2-Deoxyguanosine DNA Damage Caused by a Lucidin Analogue

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Title Synthesis and Polymerase-Mediated Bypass Studies of the N-2-Deoxyguanosine DNA Damage Caused by a Lucidin Analogue
 
Creator GHODKE, PP
HARIKRISHNA, S
PRADEEPKUMAR, PI
 
Subject I KLENOW FRAGMENT
RUBIA-TINCTORUM L
CHEMICAL CARCINOGENS
SEQUENCE CONTEXT
FORCE-FIELD
ADDUCTS
REPLICATION
FIDELITY
OLIGONUCLEOTIDES
MOLECULES
 
Description 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 (Delta T-m similar to 5 degrees 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.
 
Publisher AMER CHEMICAL SOC
 
Date 2016-01-15T06:28:38Z
2016-01-15T06:28:38Z
2015
 
Type Article
 
Identifier JOURNAL OF ORGANIC CHEMISTRY, 80(4)2128-2138
0022-3263
http://dx.doi.org/10.1021/jo502627b
http://dspace.library.iitb.ac.in/jspui/handle/100/17933
 
Language en