IMMUNOLOGY: Completing the SET

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Science  21 Feb 2003:
Vol. 299, Issue 5610, pp. 1151c
DOI: 10.1126/science.299.5610.1151c

Lymphocytes with cytotoxic activity induce cell death by delivering pro-apoptotic granzymes to the cytosol of target cells. One of the two principle granzymes, granzyme A, operates independently of caspase activation and appears to disrupt nuclear integrity and damage single-stranded DNA.

Having already identified an endoplasmic reticulum- associated protein complex, called SET, as a target of granzyme A, Fan et al. provide further insight into how interference with this complex promotes apoptosis. Apurinic endonuclease-1 (Ape-1), a DNA binding protein possessing endonuclease and redox activities, was isolated from the SET complex and shown to be cleaved upon exposure to granzyme A. As a result, two putative anti-apoptotic processes of Ape-1 were disrupted: the repair of abasic sites in DNA and the ability to mediate oxidative repair of transcription factors. Disruption of Ape-1 expression in cell lines by RNA interference enhanced apoptosis, whereas transfection with a noncleavable form of Ape-1 protected cells from granzyme A-induced cell death. Granzyme A may thus operate through the combined effects of disrupting the cellular repair activities of Ape-1 and of other members of the SET complex. — SJS

Nature Immunol. 4, 145 (2003).

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