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J. Biol. Chem., Vol. 278, Issue 11, 9378-9381, March 14, 2003

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Mode of Inhibition of Short-patch Base Excision Repair by Thymine Glycol within Clustered DNA Lesions^*

Helen Budworth^§ and Grigory L. Dianov^¶

From the  Medical Research Council Radiation and Genome Stability Unit, Harwell, Oxfordshire OX11 0RD, United Kingdom and the ^§ Biochemistry Department, University of Oxford, Oxford OX1 3QU, United Kingdom

Clustered DNA damage, where two or more lesions are located proximally to each other, is frequently induced by ionizing radiation. Individual base lesions within a cluster are repaired by base excision repair. In this study we addressed the question of how thymine glycol (Tg) within a cluster would affect the repair of opposing lesions by human cell extracts. We have found that Tg located opposite to an abasic site does not affect cleavage of this site by apurinic/apyrimidinic (AP) endonuclease. However, Tg significantly compromised the next step of the repair. Although purified DNA polymerase  was able to incorporate the correct nucleotide (dAMP) opposite to Tg, the rate of incorporation was reduced by 3-fold. Tg does not affect 5'-sugar phosphate removal by the 2-deoxyribose-5-phosphate (dRP) lyase activity of DNA polymerase , but further processing of the strand break by purified DNA ligase III was slightly diminished. In agreement with these findings, although an AP site located opposite to Tg was efficiently incised in human cell extract, only a limited amount of fully repaired product was observed, suggesting that such clustered DNA lesions may have a significantly increased lifetime in human cells compared with similar single-standing lesions.

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