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P. 93
termination and DSB repair. Mice deficient in K-H were embryonic lethal, but heterozygotes show haplo-
insufficiencies, with elevated R-loops, DSBs, and loss of Artemis. While unchallenged mice showed no
increase in cancer formation, exposure of the mice to IR (1-7 Gy) resulted in significant induction of
lymphoma. The effects of loss or SNPs in K-H in humans will be discussed. This research was supported by
NIH/NCI grant CA 5R01 CA139217-04 to DAB and an NIH/NCI minority supplement to EM.
S26 DNA DAMAGE: FROM CHEMISTRY TO THERAPY
The various biological effects of ionizing radiation are thought to result from chemical
modifications in DNA, initiated by free radical interactions. The symposium spans DNA damage through
to potential therapeutic uses by focusing on novel radiation lesions, DNA damage transfer, low energy
electron damage and chemo-radiotherapy and finally the potential use of small molecule inhibitors of
DNA repair and potentially clinical uses.
1
(S2601) An exploration of low-energy radiation-induced DNA damage. Amanda Bryant-Friedrich ;
2
1
2
Buthina Al-Oudat, PhD ; Suaad Audat, PhD ; and Prajakta S. Bhatkhande, University of Toledo, Toledo,
2
1
OH and Jordanian University of Science and Technology, Irbid, Jordan
The direct ionization/excitation of all constituents of DNA (the direct effect) is accompanied by
the formation of a significant amount of ions and secondary low energy electrons. These low energy
electrons or LEEs with energies between 10-30 eV, are highly attractive to biological molecules and have
also been shown to cause their ionization as well as excitation. While the nucleobases of DNA receive the
brunt of the attack during the direct effect, a noteworthy amount of damage is also found to result from
the formation of radical species at the 2-deoxyribose moiety of DNA. This damage is of significance as it
primarily leads to DNA strand breaks. Even though a significant amount of effort has been devoted to the
identification of products resulting from LEEs and the elucidation of the mechanisms, which contribute to
their formation, a dearth of information still exist in this arena. In landmark studies performed in the
Sanche laboratory, it was shown that two significant 2-deoxyribose centered radicals form when LEEs of
0ā3 eV are initially captured by the nucleobases of DNA giving a transient negative ion of which the
electron transfers to the phosphate moiety causing the CāO bond to break via dissociative electron
attachment. These radicals are the 2', 3ā- and 2', 5ā-dideoxynucleoside radicals. Our laboratory has
synthesized photolabile precursors of these radicals and explored their reactivity under anaerobic
conditions in the presence of a reductant. The precursors, which have also been incorporated into
oligonucleotides, have been used to show that the primary products of these radicals under the conditions
described are the 3'- and 5'-deoxyribose nucleoside and nucleotide products. Utilizing these tools, we
have embarked on an extensive study to determine the fate of the radicals of interest under a variety of
biologically relevant conditions. The outcome of these studies will be discussed.
91 | P a g e
insufficiencies, with elevated R-loops, DSBs, and loss of Artemis. While unchallenged mice showed no
increase in cancer formation, exposure of the mice to IR (1-7 Gy) resulted in significant induction of
lymphoma. The effects of loss or SNPs in K-H in humans will be discussed. This research was supported by
NIH/NCI grant CA 5R01 CA139217-04 to DAB and an NIH/NCI minority supplement to EM.
S26 DNA DAMAGE: FROM CHEMISTRY TO THERAPY
The various biological effects of ionizing radiation are thought to result from chemical
modifications in DNA, initiated by free radical interactions. The symposium spans DNA damage through
to potential therapeutic uses by focusing on novel radiation lesions, DNA damage transfer, low energy
electron damage and chemo-radiotherapy and finally the potential use of small molecule inhibitors of
DNA repair and potentially clinical uses.
1
(S2601) An exploration of low-energy radiation-induced DNA damage. Amanda Bryant-Friedrich ;
2
1
2
Buthina Al-Oudat, PhD ; Suaad Audat, PhD ; and Prajakta S. Bhatkhande, University of Toledo, Toledo,
2
1
OH and Jordanian University of Science and Technology, Irbid, Jordan
The direct ionization/excitation of all constituents of DNA (the direct effect) is accompanied by
the formation of a significant amount of ions and secondary low energy electrons. These low energy
electrons or LEEs with energies between 10-30 eV, are highly attractive to biological molecules and have
also been shown to cause their ionization as well as excitation. While the nucleobases of DNA receive the
brunt of the attack during the direct effect, a noteworthy amount of damage is also found to result from
the formation of radical species at the 2-deoxyribose moiety of DNA. This damage is of significance as it
primarily leads to DNA strand breaks. Even though a significant amount of effort has been devoted to the
identification of products resulting from LEEs and the elucidation of the mechanisms, which contribute to
their formation, a dearth of information still exist in this arena. In landmark studies performed in the
Sanche laboratory, it was shown that two significant 2-deoxyribose centered radicals form when LEEs of
0ā3 eV are initially captured by the nucleobases of DNA giving a transient negative ion of which the
electron transfers to the phosphate moiety causing the CāO bond to break via dissociative electron
attachment. These radicals are the 2', 3ā- and 2', 5ā-dideoxynucleoside radicals. Our laboratory has
synthesized photolabile precursors of these radicals and explored their reactivity under anaerobic
conditions in the presence of a reductant. The precursors, which have also been incorporated into
oligonucleotides, have been used to show that the primary products of these radicals under the conditions
described are the 3'- and 5'-deoxyribose nucleoside and nucleotide products. Utilizing these tools, we
have embarked on an extensive study to determine the fate of the radicals of interest under a variety of
biologically relevant conditions. The outcome of these studies will be discussed.
91 | P a g e
