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J. Biol. Chem., Vol. 283, Issue 32, 21873-21880, August 8, 2008

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CCCTC-binding Factor Activates PARP-1 Affecting DNA Methylation Machinery^*

Tiziana Guastafierro¹, Barbara Cecchinelli¹², Michele Zampieri³, Anna Reale, Giuseppe Riggio, Olga Sthandier, Gabriella Zupi^¶4, Lilia Calabrese^||, and Paola Caiafa⁴⁵

From the Departments of Cellular Biotechnology and Haematology and ^||Biochemical Sciences, University "La Sapienza", Piazzale Aldo Moro 5, 00161 Rome, Pasteur Institute-Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, 00161 Rome, and ^¶Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, via delle Messi d' Oro 156, 00158 Rome, Italy

Our previous data have shown that in L929 mouse fibroblasts the control of methylation pattern depends in part on poly(ADP-ribosyl)ation and that ADP-ribose polymers (PARs), both present on poly(ADP-ribosyl)ated PARP-1 and/or protein-free, have an inhibitory effect on Dnmt1 activity. Here we show that transient ectopic overexpression of CCCTC-binding factor (CTCF) induces PAR accumulation, PARP-1, and CTCF poly(ADP-ribosyl)ation in the same mouse fibroblasts. The persistence in time of a high PAR level affects the DNA methylation machinery; the DNA methyltransferase activity is inhibited with consequences for the methylation state of genome, which becomes diffusely hypomethylated affecting centromeric minor satellite and B1 DNA repeats. In vitro data show that CTCF is able to activate PARP-1 automodification even in the absence of nicked DNA. Our new finding that CTCF is able per se to activate PARP-1 automodification in vitro is of great interest as so far a burst of poly(ADP-ribosyl)ated PARP-1 has generally been found following introduction of DNA strand breaks. CTCF is unable to inhibit DNMT1 activity, whereas poly(ADP-ribosyl)ated PARP-1 plays this inhibitory role. These data suggest that CTCF is involved in the cross-talk between poly(ADP-ribosyl)ation and DNA methylation and underscore the importance of a rapid reversal of PARP activity, as DNA methylation pattern is responsible for an important epigenetic code.

Received for publication, February 12, 2008 , and in revised form, May 29, 2008.

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^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures and Fig. S1.

¹ Both authors contributed equally to this work.

² Present address: Dept. of Experimental Medicine and Pathology, II Faculty of Medicine, University "La Sapienza," 00100 Rome, Italy.

³ Supported by Associazione Italiana per la Ricerca sul Cancro fellowship.

⁴ Supported in part by Ministero della Salute.

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⁵ To whom correspondence should be addressed: Dept. of Cellular Biotechnology and Haematology, University "La Sapienza", viale Regina Elena 324, 00161 Rome, Italy. Tel.: 390649976530; Fax: 390644231961; E-mail: caiafa{at}bce.uniroma1.it.

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