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J. Biol. Chem., Vol. 276, Issue 14, 11279-11286, April 6, 2001
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From the DNA Repair Group, Health and Environment Unit,
Laval University Medical Centre, CHUQ, Faculty of Medicine, Laval
University, Ste-Foy, Quebec G1V 4G2, Canada
Poly(ADP-ribose) polymerase is a 113-kDa nuclear
enzyme that 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 we 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.
Functional Competition between Poly(ADP-ribose) Polymerase and
Its 24-kDa Apoptotic Fragment in DNA Repair and Transcription*
*
This work was supported in part by the National Cancer
Institute of Canada for the Terry Fox Run and the Canadian Institutes of Health Research; The Canada Foundation for Innovation and the Quebec government provided infrastructure support.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a salary support award from the Canadian
Institutes of Health Research. To whom correspondence
should be addressed: DNA Repair Group, Health and Environment Unit,
Laval University Medical Centre, CHUQ, Faculty of Medicine, Laval
University, 2705 Blvd. Laurier, Ste-Foy, Quebec G1V 4G2, Canada. Tel.:
418-656-4141 (Ext. 7340); Fax: 418-654-2159; E-mail:
Masahiko.sato@crchul.ulaval.ca.
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