Abstract
N3-methyladenine (3-mA) is a cytotoxic lesion formed by the reaction of DNA with many methylating agents, including antineoplastic drugs, environmental agents and endogenously generated compounds. The toxicity of 3-mA has been attributed to its ability to block DNA polymerization. Using Me-lex, a compound that selectively and efficiently reacts with DNA to afford 3-mA, we have observed in yeast a mutational hotspot at the 5′ -terminus of an A 4 tract. In order to explore the potential role of sequence-dependent DNA polymerase bypass of 3-mA, we developed an in vitro system to prepare 3-mA modified substrates using Me-lex. We detail the effects of 3-mA, its stable isostere analogue, 3-methyl-3-deazaadenine, 3-deazaadenine and an THF abasic site on DNA polymerization within an A4 sequence. The methyl group on 3-mA and 3-methyl-3-deazaadenine has a pronounced inhibitory effect on DNA polymerization. There was no sequence selectivity for the bypass of any of the lesions, except for the abasic site, which was most efficiently by-passed when it was on the 5′ -terminus of the A4 tract. The results indicate that the weak mutational pattern induced by Me-lex may result form the depurination of 3-mA to an abasic site that is bypassed in a sequence dependent context.
| Original language | English |
|---|---|
| Article number | 426505 |
| Journal | Journal of Nucleic Acids |
| Volume | 2010 |
| DOIs | |
| Publication status | Published - 2010 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
Cite this
Effect of N3-methyladenine and an isosteric stable analogue on DNA polymerization. / Settles, Samuel; Wang, Ruo Wen; Fronza, Gilberto; Gold, Barry.
In: Journal of Nucleic Acids, Vol. 2010, 426505, 2010.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Effect of N3-methyladenine and an isosteric stable analogue on DNA polymerization
AU - Settles, Samuel
AU - Wang, Ruo Wen
AU - Fronza, Gilberto
AU - Gold, Barry
PY - 2010
Y1 - 2010
N2 - N3-methyladenine (3-mA) is a cytotoxic lesion formed by the reaction of DNA with many methylating agents, including antineoplastic drugs, environmental agents and endogenously generated compounds. The toxicity of 3-mA has been attributed to its ability to block DNA polymerization. Using Me-lex, a compound that selectively and efficiently reacts with DNA to afford 3-mA, we have observed in yeast a mutational hotspot at the 5′ -terminus of an A 4 tract. In order to explore the potential role of sequence-dependent DNA polymerase bypass of 3-mA, we developed an in vitro system to prepare 3-mA modified substrates using Me-lex. We detail the effects of 3-mA, its stable isostere analogue, 3-methyl-3-deazaadenine, 3-deazaadenine and an THF abasic site on DNA polymerization within an A4 sequence. The methyl group on 3-mA and 3-methyl-3-deazaadenine has a pronounced inhibitory effect on DNA polymerization. There was no sequence selectivity for the bypass of any of the lesions, except for the abasic site, which was most efficiently by-passed when it was on the 5′ -terminus of the A4 tract. The results indicate that the weak mutational pattern induced by Me-lex may result form the depurination of 3-mA to an abasic site that is bypassed in a sequence dependent context.
AB - N3-methyladenine (3-mA) is a cytotoxic lesion formed by the reaction of DNA with many methylating agents, including antineoplastic drugs, environmental agents and endogenously generated compounds. The toxicity of 3-mA has been attributed to its ability to block DNA polymerization. Using Me-lex, a compound that selectively and efficiently reacts with DNA to afford 3-mA, we have observed in yeast a mutational hotspot at the 5′ -terminus of an A 4 tract. In order to explore the potential role of sequence-dependent DNA polymerase bypass of 3-mA, we developed an in vitro system to prepare 3-mA modified substrates using Me-lex. We detail the effects of 3-mA, its stable isostere analogue, 3-methyl-3-deazaadenine, 3-deazaadenine and an THF abasic site on DNA polymerization within an A4 sequence. The methyl group on 3-mA and 3-methyl-3-deazaadenine has a pronounced inhibitory effect on DNA polymerization. There was no sequence selectivity for the bypass of any of the lesions, except for the abasic site, which was most efficiently by-passed when it was on the 5′ -terminus of the A4 tract. The results indicate that the weak mutational pattern induced by Me-lex may result form the depurination of 3-mA to an abasic site that is bypassed in a sequence dependent context.
UR - http://www.scopus.com/inward/record.url?scp=79960698136&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960698136&partnerID=8YFLogxK
U2 - 10.4061/2010/426505
DO - 10.4061/2010/426505
M3 - Article
VL - 2010
JO - Journal of Nucleic Acids
JF - Journal of Nucleic Acids
SN - 2090-0201
M1 - 426505
ER -