16 Citations (Scopus)

Abstract

Depurinating DNA adducts formed by aromatic hydrocarbons and catechol estrogen quinones play a major role in cancer initiation. Most of these adducts depurinate instantaneously, but some guanine adducts depurinate from DNA with half-lives of hours. We report here, that after 10 h at 37 °C, reaction of estradiol-3,4-quinone (E 2-3,4-Q) with ds-DNA to yield N7Gua and N3Ade adducts was complete and more efficient than with ss-DNA. When E 2-3,4-Q reacted with t-RNA, no adducts were detected after 10 h, and the level of N3Ade and N7Gua adducts after 10 days was less than half that with ss-DNA after 10 h. Reaction of E 2-3,4-Q and dG yielded 4-OHE 2-1-N7dG, which spontaneously depurinated to yield 4-OHE 2-1-N7Gua. To investigate the mechanism of depurination, E 2-3,4-Q was reacted with carbocyclicdeoxyguanosine, in which the ring oxygen of the deoxyribose moiety is substituted with CH 2, and depurination was observed. The results from this experiment demonstrate that the oxocarbenium ion mechanism plays the major role in depurination and provides the first experimental evidence for this mechanism. A newly discovered β-elimination mechanism also plays a minor role in depurination. Understanding why the depurinating estrogen-DNA adducts come from DNA, and not from RNA, underscores the critical role that these adducts play in initiating cancer.

Original languageEnglish (US)
Pages (from-to)169-179
Number of pages11
JournalIUBMB Life
Volume64
Issue number2
DOIs
StatePublished - Feb 1 2012

Fingerprint

Carcinogens
DNA Adducts
DNA
Neoplasms
Catechol Estrogens
RNA
Deoxyribose
Aromatic Hydrocarbons
Quinones
Guanine
Estrogens
Ions
Oxygen
Experiments

Keywords

  • catechol estrogen-3,4-quinones
  • depurinating adducts
  • estrogen-DNA adducts
  • mechanism of depurination

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Clinical Biochemistry
  • Cell Biology

Cite this

Mechanism of DNA depurination by carcinogens in relation to cancer initiation. / Cavalieri, Ercole; Saeed, Muhammad; Zahid, Muhammad; Cassada, David; Snow, Daniel D; Miljkovic, Momcilo; Rogan, Eleanor G.

In: IUBMB Life, Vol. 64, No. 2, 01.02.2012, p. 169-179.

Research output: Contribution to journalArticle

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abstract = "Depurinating DNA adducts formed by aromatic hydrocarbons and catechol estrogen quinones play a major role in cancer initiation. Most of these adducts depurinate instantaneously, but some guanine adducts depurinate from DNA with half-lives of hours. We report here, that after 10 h at 37 °C, reaction of estradiol-3,4-quinone (E 2-3,4-Q) with ds-DNA to yield N7Gua and N3Ade adducts was complete and more efficient than with ss-DNA. When E 2-3,4-Q reacted with t-RNA, no adducts were detected after 10 h, and the level of N3Ade and N7Gua adducts after 10 days was less than half that with ss-DNA after 10 h. Reaction of E 2-3,4-Q and dG yielded 4-OHE 2-1-N7dG, which spontaneously depurinated to yield 4-OHE 2-1-N7Gua. To investigate the mechanism of depurination, E 2-3,4-Q was reacted with carbocyclicdeoxyguanosine, in which the ring oxygen of the deoxyribose moiety is substituted with CH 2, and depurination was observed. The results from this experiment demonstrate that the oxocarbenium ion mechanism plays the major role in depurination and provides the first experimental evidence for this mechanism. A newly discovered β-elimination mechanism also plays a minor role in depurination. Understanding why the depurinating estrogen-DNA adducts come from DNA, and not from RNA, underscores the critical role that these adducts play in initiating cancer.",
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AU - Cavalieri, Ercole

AU - Saeed, Muhammad

AU - Zahid, Muhammad

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AU - Snow, Daniel D

AU - Miljkovic, Momcilo

AU - Rogan, Eleanor G

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N2 - Depurinating DNA adducts formed by aromatic hydrocarbons and catechol estrogen quinones play a major role in cancer initiation. Most of these adducts depurinate instantaneously, but some guanine adducts depurinate from DNA with half-lives of hours. We report here, that after 10 h at 37 °C, reaction of estradiol-3,4-quinone (E 2-3,4-Q) with ds-DNA to yield N7Gua and N3Ade adducts was complete and more efficient than with ss-DNA. When E 2-3,4-Q reacted with t-RNA, no adducts were detected after 10 h, and the level of N3Ade and N7Gua adducts after 10 days was less than half that with ss-DNA after 10 h. Reaction of E 2-3,4-Q and dG yielded 4-OHE 2-1-N7dG, which spontaneously depurinated to yield 4-OHE 2-1-N7Gua. To investigate the mechanism of depurination, E 2-3,4-Q was reacted with carbocyclicdeoxyguanosine, in which the ring oxygen of the deoxyribose moiety is substituted with CH 2, and depurination was observed. The results from this experiment demonstrate that the oxocarbenium ion mechanism plays the major role in depurination and provides the first experimental evidence for this mechanism. A newly discovered β-elimination mechanism also plays a minor role in depurination. Understanding why the depurinating estrogen-DNA adducts come from DNA, and not from RNA, underscores the critical role that these adducts play in initiating cancer.

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