DNA Damage and Cytotoxicity Induced by Minor Groove Binding Methyl Sulfonate Esters

Sridhar Varadarajan, Dharini Shah, Prasad Dande, Samuel Settles, Fa Xian Chen, Gilberto Fronza, Barry Gold

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Minor groove specific DNA equilibrium binding peptides (lex) based on N-methylpyrrole-carboxamide and/or N-methylimidazolecarboxamide subunits have been modified with an O-methyl sulfonate ester functionality to target DNA methylation in the minor groove at Ade/Thy- and/or Gua/ Cyt-rich sequences. HPLC and sequencing gel analyses show that the Me-lex compounds all selectively react with DNA to afford N3-alkyladenine as a major adduct. The formation of the N3-alkyladenine lesions is sequence-dependent based on the equilibrium binding preferences of the different lex peptides. In addition to the reaction at adenine, the molecules designed to target Gua/Cyt sequences also generate lesions at guanine; however, the methylation is not sequence dependent and takes places in the major groove at the N7-position. To determine if and how the level of the different DNA adducts and the sequence selectivity for their formation affects cytotoxicity, the Me-lex analogues were tested in wild type Escherichia coli and in mutant strains defective in base excision repair (tag and/or alkA or apn). The results demonstrate the importance of 3-methyladenine, and in some cases 3-methylguanine, lesions in cellular toxicity, and the dominant protective role of the DNA glycosylases. There is no evidence that the sequence specificity is related to toxicity.

Original languageEnglish
Pages (from-to)14318-14327
Number of pages10
JournalBiochemistry
Volume42
Issue number48
DOIs
Publication statusPublished - Dec 9 2003

Fingerprint

Cytotoxicity
DNA Damage
Toxicity
Esters
DNA Glycosylases
Peptides
Methylation
DNA Adducts
DNA
Guanine
Adenine
DNA Methylation
DNA Repair
Escherichia coli
Repair
Gels
High Pressure Liquid Chromatography
Molecules
methyl lexitropsin
N-methylpyrrole

ASJC Scopus subject areas

  • Biochemistry

Cite this

Varadarajan, S., Shah, D., Dande, P., Settles, S., Chen, F. X., Fronza, G., & Gold, B. (2003). DNA Damage and Cytotoxicity Induced by Minor Groove Binding Methyl Sulfonate Esters. Biochemistry, 42(48), 14318-14327. https://doi.org/10.1021/bi0353272

DNA Damage and Cytotoxicity Induced by Minor Groove Binding Methyl Sulfonate Esters. / Varadarajan, Sridhar; Shah, Dharini; Dande, Prasad; Settles, Samuel; Chen, Fa Xian; Fronza, Gilberto; Gold, Barry.

In: Biochemistry, Vol. 42, No. 48, 09.12.2003, p. 14318-14327.

Research output: Contribution to journalArticle

Varadarajan, S, Shah, D, Dande, P, Settles, S, Chen, FX, Fronza, G & Gold, B 2003, 'DNA Damage and Cytotoxicity Induced by Minor Groove Binding Methyl Sulfonate Esters', Biochemistry, vol. 42, no. 48, pp. 14318-14327. https://doi.org/10.1021/bi0353272
Varadarajan S, Shah D, Dande P, Settles S, Chen FX, Fronza G et al. DNA Damage and Cytotoxicity Induced by Minor Groove Binding Methyl Sulfonate Esters. Biochemistry. 2003 Dec 9;42(48):14318-14327. https://doi.org/10.1021/bi0353272
Varadarajan, Sridhar ; Shah, Dharini ; Dande, Prasad ; Settles, Samuel ; Chen, Fa Xian ; Fronza, Gilberto ; Gold, Barry. / DNA Damage and Cytotoxicity Induced by Minor Groove Binding Methyl Sulfonate Esters. In: Biochemistry. 2003 ; Vol. 42, No. 48. pp. 14318-14327.
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