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An exonucleolytic activity of human apurinic/apyrimidinic endonuclease on 3′ mispaired DNA


Human apurinic/apyrimidinic endonuclease (APE1) is an essential enzyme in DNA base excision repair that cuts the DNA backbone immediately adjacent to the 5′ side of abasic sites to facilitate repair synthesis by DNA polymerase β (ref. 1). Mice lacking the murine homologue of APE1 die at an early embryonic stage2. Here we report that APE1 has a DNA exonuclease activity on mismatched deoxyribonucleotides at the 3′ termini of nicked or gapped DNA molecules. The efficiency of this activity is inversely proportional to the gap size in DNA. In a base excision repair system reconstituted in vitro, the rejoining of nicked mismatched DNA depended on the presence of APE1, indicating that APE1 may increase the fidelity of base excision repair and may represent a new 3′ mispaired DNA repair mechanism. The exonuclease activity of APE1 can remove the anti-HIV nucleoside analogues 3′-azido-3′-deoxythymidine and 2′,3′-didehydro-2′, 3′-dideoxythymidine from DNA, suggesting that APE1 might have an impact on the therapeutic index of antiviral compounds in this category.

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Figure 1: Rate of APE1 exonucelase activity on different DNA substrates.
Figure 2: Activity of APE1 mismatch repair on DNA with different gap sizes.
Figure 3: In vitro reconstitution of the BER system.
Figure 4: The contribution of APE1 exonuclease to removal of DNA 3′ mispairs in nuclear extracts of human cells.


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We thank Z. Hatahet and J. B. Sweasy for discussion; M. Kelley and B. Demple for providing the APE clones; A. Tomkinson for human DNA ligase I; and J. Sweasy for human DNA polymerase β.

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Correspondence to Yung-Chi Cheng.

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Chou, KM., Cheng, YC. An exonucleolytic activity of human apurinic/apyrimidinic endonuclease on 3′ mispaired DNA. Nature 415, 655–659 (2002).

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