Nature Immunology
4, 145 - 153 (2003)
Published online: 13 January 2003; | doi:10.1038/ni885
Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme AZusen Fan1, 2, Paul J. Beresford1, 2, Dong Zhang1, 2, Zhan Xu1, Carl D. Novina3, Akira Yoshida4, 5, Yves Pommier4
& Judy Lieberman1, 21
Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA. 2
Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. 3
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. 4
Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, MD 20892, USA. 5
Present address: Department of Internal Medicine, Fukui Medical University, Matsuoka 910-1193, Japan.
Correspondence should be addressed to Judy Lieberman lieberman@cbr.med.harvard.eduThe cytolytic T lymphocyte protease granzyme A (GzmA) initiates a caspase-independent cell death pathway. Here we report that the rate-limiting enzyme of DNA base excision repair, apurinic endonuclease-1 (Ape1), which is also known as redox factor-1 (Ref-1), binds to GzmA and is contained in the SET complex, a macromolecular complex of 270−420 kDa that is associated with the endoplasmic reticulum and is targeted by GzmA during cell-mediated death. GzmA cleaves Ape1 after Lys31 and destroys its known oxidative repair functions. In so doing, GzmA may block cellular repair and force apoptosis. In support of this, cells with silenced Ape1 expression are more sensitive, whereas cells overexpressing noncleavable Ape1 are more resistant, to GzmA-mediated death.
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