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Blood, 6 August 2009, Vol. 114, No. 6, pp. 1205-1216. Prepublished online as a Blood First Edition Paper on June 8, 2009; DOI 10.1182/blood-2008-12-195768. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2008-12-195768v1 114/6/1205    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zhu, P. Articles by Lieberman, J. Search for Related Content PubMed PubMed Citation Articles by Zhu, P. Articles by Lieberman, J. Related Collections Immunobiology Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY The cytotoxic T lymphocyte protease granzyme A cleaves and inactivates poly(adenosine 5'-diphosphate-ribose) polymerase-1 Pengcheng Zhu1,*, Denis Martinvalet1,*, Dipanjan Chowdhury1, Dong Zhang1, Ann Schlesinger1, and Judy Lieberman1 1 Immune Disease Institute and Department of Pediatrics, Harvard Medical School, Boston, MA Granzyme A (GzmA) in killer cells induces caspase-independent programmed cell death. In this study, we show that GzmA cleaves the DNA damage sensor poly(adenosine 5'-diphosphate-ribose) polymerase-1 (PARP-1) after Lys498 in its automodification domain, separating the DNA binding domain from the catalytic domain, which interferes with repair of GzmA-induced DNA damage and enhances susceptibility to GzmA-mediated death. Overexpressing K498A PARP-1 reduces GzmA-mediated death and drives dying cells to necrosis rather than apoptosis. Conversely, inhibiting or genetically disrupting PARP-1 enhances cell vulnerability. The N-terminal GzmA cleavage fragment of PARP-1 acts as a PARP-1 dominant negative, binding to DNA and blocking DNA repair. Disrupting PARP-1, which is also a caspase target, is therefore required for efficient apoptosis by both caspase-independent and caspase-dependent pathways. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: Granzyme A is a proinflammatory protease Julián Pardo, Markus M. Simon, and Christopher J. Froelich Blood 2009 114: 3968. [Full Text] [PDF] Response: Granzyme A: cell death–inducing protease, proinflammatory agent, or both? Denis Martinvalet, Michael Walch, Danielle K. Jensen, Jerome Thiery, and Judy Lieberman Blood 2009 114: 3969-3970. [Full Text] [PDF] This article has been cited by other articles: J. Pardo, M. M. Simon, and C. J. Froelich Granzyme A is a proinflammatory protease Blood, October 29, 2009; 114(18): 3968 - 3968. [Full Text] [PDF] D. Martinvalet, M. Walch, D. K. Jensen, J. Thiery, and J. Lieberman Response: Granzyme A: cell death-inducing protease, proinflammatory agent, or both? Blood, October 29, 2009; 114(18): 3969 - 3970. [Full Text] [PDF]

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