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Papers In Press, published online ahead of print December 20, 2000
J. Biol. Chem, 10.1074/jbc.M008044200
Submitted on September 1, 2000
Revised on December 12, 2000
Accepted on December 19, 2000
Anatomy, CHUL Research Center, Laval University, Ste-Foy, QC G1V 4G2
Corresponding Author: Masahiko.sato{at}crchul.ulaval.ca
Poly(ADP-ribose) polymerase is a 113 kDa nuclear enzyme which binds to both damaged DNA and to RNA associated with actively transcribed regions of chromatin. Binding of poly(ADP-ribose) polymerase to DNA lesions activates it, catalyzing the covalent addition of multiple ADP-ribose polymers to the enzyme (automodification). During apoptosis, poly(ADP-ribose) polymerase is cleaved by caspase-3, resulting in the formation of an N-terminal 24 kDa fragment, containing the DNA binding domain, and a C-terminal 89 kDa catalytic fragment. The functional relevance of this cleavage is not well understood. We therefore prepared a recombinant 24 kDa poly(ADP-ribose) polymerase fragment and investigated the role of this fragment in DNA repair and transcription. The 24 kDa fragment retained its binding affinity for both DNA breaks and RNA. In an in vitro cell-free DNA repair assay, this fragment inhibited rejoining of DNA breaks and suppressed ADP-ribose polymer formation by competing with poly(ADP-ribose) polymerase in binding to DNA breaks. With regard to transcription, it has recently been demonstrated that binding of poly(ADP-ribose) polymerase to transcribed RNA reduces the rate of transcript elongation and that automodification of poly(ADP-ribose) polymerase bound to DNA breaks results in up-regulation of transcription. We tested the 24 kDa fragment for its ability to suppress transcript elongation and found that it competed against the up-regulation of transcription mediated by full-length poly(ADP-ribose) polymerase. The ability of the 24 kDa fragment to inhibit DNA repair, ADP-ribose polymer formation, and damage-dependent up-regulation of transcription may contribute to the apoptotic shift from cell survival to cell death mode.
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