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J. Biol. Chem., Vol. 278, Issue 39, 37768-37776, September 26, 2003

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Human Apurinic/Apyrimidinic Endonuclease (Ape1) and Its N-terminal Truncated Form (AN34) Are Involved in DNA Fragmentation during Apoptosis^*

Akira Yoshida  , Yoshimasa Urasaki , Mark Waltham , Ann-Charlotte Bergman ¶, Philippe Pourquier , Dominic G. Rothwell ||, Manabu Inuzuka **, John N. Weinstein , Takanori Ueda , Ettore Appella ¶, Ian D. Hickson || and Yves Pommier  

From the Laboratory of Molecular Pharmacology and ^¶Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892-4255, the First Department of Internal Medicine and the ^**Department of Chemistry, Fukui Medical University, Matsuoka, Fukui, 910-1193, Japan, and the ^||Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom

We previously isolated a 34-kDa nuclease (AN34) from apoptotic human leukemia cells. Here, we identify AN34 as an N-terminally truncated form of human AP endonuclease (Ape1) lacking residues 1–35 (35-Ape1). Although Ape1 has hitherto been considered specific for damaged DNA (specific to AP site), recombinant AN34 (35-Ape1) possesses significant endonuclease activity on undamaged (normal) DNA and in chromatin. AN34 also displays enhanced 3'-5' exonuclease activity. Caspase-3 activates AN34 in a cell-free system, although caspase-3 cannot cleave Ape1 directly in vitro. We also found that Ape1 itself preferentially cleaves damaged chromatin DNA isolated from cells treated with apoptotic stimuli and that silencing of Ape1 expression decreases apoptotic DNA fragmentation in DFF40/CAD-deficient cells. Thus, we propose that AN34 and Ape1 participate in the process of chromatin fragmentation during apoptosis.

Received for publication, May 9, 2003

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Laboratory of Molecular Pharmacology, Center for Cancer Research, Bldg. 37, Rm. 5068, NCI, National Institutes of Health, Bethesda, MD 20892-4255. Tel.: 301-496-5944; Fax: 301-402-0752; E-mail: pommier{at}nih.gov.

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