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Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A

Nature Immunologyvolume 4pages145153 (2003) | Download Citation



The 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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We thank M. Russo for technical support; B. Demple, D. Oh, X.-F. Yang, L. Shi and K. Kaznatcheev for suggestions; and the National Center for Cell Culture for preparing K562 cell lysates to purify the SET complex. This work was supported by a grant from the National Institutes of Health (NIH) to J.L. and the NIH-supported Dana Farber Cancer Institute, Beth Israel Deaconess Medical Center and Children's Hospital Center for AIDS Research.

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Author notes

    • Akira Yoshida

    Present address: Department of Internal Medicine, Fukui Medical University, Matsuoka, 910-1193, Japan


  1. Center for Blood Research, Harvard Medical School, Boston, 02115, MA, USA

    • Zusen Fan
    • , Paul J. Beresford
    • , Dong Zhang
    • , Zhan Xu
    •  & Judy Lieberman
  2. Department of Pediatrics, Harvard Medical School, Boston, 02115, MA, USA

    • Zusen Fan
    • , Paul J. Beresford
    • , Dong Zhang
    •  & Judy Lieberman
  3. Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139, MA, USA

    • Carl D. Novina
  4. Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, 20892, MD, USA

    • Akira Yoshida
    •  & Yves Pommier


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The authors declare no competing financial interests.

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Correspondence to Judy Lieberman.

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