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C100577200v1
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Papers In Press, published online ahead of print January 22, 2002
J. Biol. Chem, 10.1074/jbc.C100577200
Submitted on October 5, 2001
Revised on January 7, 2002
Accepted on January 18, 2002

Covalent trapping of human DNA polymerase beta by the oxidative DNA lesion 2-deoxyribonolactone

Michael S. DeMott, Ergin Beyret, Donny Wong, Brian C. Bales, Jae T. Hwang, Marc M. Greenberg, and Bruce Demple

Cancer Cell Biology, Harvard School of Public Health, Boston, MA 02115

Corresponding Author: bdemple{at}hsph.harvard.edu

Oxidized abasic residues in DNA constitute a major class of radiation and oxidative damage. Free radical attack on the nucleotidyl C1' carbon yield 2-deoxyribonolactone (dL) as a significant lesion. Although dL residues are efficiently incised by the main human abasic endonuclease enzyme Ape1, we show here that subsequent excision by human DNA polymerase beta is strongly inhibited compared to unmodified abasic sites. This inhibition is accompanied by accumulation of a protein-DNA cross-link not observed in reactions of polymerase beta with unmodified abasic sites, although a similar form can be trapped by reduction with sodium borohydride. The formation of the stably cross-linked species with dL depends on the polymerase lysine-72 residue, which forms a Schiff base with the C1-aldehyde during excision of an unmodified abasic site. In the case of a dL residue, attack on the lactone C1 by lysine-72 proceeds more slowly and evidently produces an amide linkage, which resists further processing. Consequently, dL residues appear not to be readily repaired by "short-patch" base excision repair but instead function as suicide substrates in the formation of a protein-DNA cross-link that may require alternative modes of repair.


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