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Molecular and Cellular Biology, February 2004, p. 1595-1607, Vol. 24, No. 4
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.4.1595-1607.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Functional Interaction between Poly(ADP-Ribose) Polymerase 2 (PARP-2) and TRF2: PARP Activity Negatively Regulates TRF2

Françoise Dantzer,1,{dagger} Marie-Josèphe Giraud-Panis,2,{dagger} Isabel Jaco,3,{dagger} Jean-Christophe Amé,1 Inès Schultz,1 Maria Blasco,3 Catherine-Elaine Koering,4 Eric Gilson,4 Josiane Ménissier-de Murcia,1 Gilbert de Murcia,1 and Valérie Schreiber1*

UPR 9003 du Centre National de la Recherche Scientifique, Université Louis Pasteur, Ecole Supérieure de Biotechnologie de Strasbourg, 67412 Illkirch Cedex,1 UPR4301/CNRS, CBM, F-45071 Orléans,2 UMR5161/CNRS, ENS de Lyon, F-69364 Lyon, France,4 Department of Immunology and Oncology, National Center of Biotechnology, CSIC, Campus de Cantoblanco, Madrid E-28049, Spain3

Received 4 April 2003/ Returned for modification 12 May 2003/ Accepted 13 November 2003

The DNA damage-dependent poly(ADP-ribose) polymerase-2 (PARP-2) is, together with PARP-1, an active player of the base excision repair process, thus defining its key role in genome surveillance and protection. Telomeres are specialized DNA-protein structures that protect chromosome ends from being recognized and processed as DNA strand breaks. In mammals, telomere protection depends on the T2AG3 repeat binding protein TRF2, which has been shown to remodel telomeres into large duplex loops (t-loops). In this work we show that PARP-2 physically binds to TRF2 with high affinity. The association of both proteins requires the N-terminal domain of PARP-2 and the myb domain of TRF2. Both partners colocalize at promyelocytic leukemia bodies in immortalized telomerase-negative cells. In addition, our data show that PARP activity regulates the DNA binding activity of TRF2 via both a covalent heteromodification of the dimerization domain of TRF2 and a noncovalent binding of poly(ADP-ribose) to the myb domain of TRF2. PARP-2-/- primary cells show normal telomere length as well as normal telomerase activity compared to wild-type cells but display a spontaneously increased frequency of chromosome and chromatid breaks and of ends lacking detectable T2AG3 repeats. Altogether, these results suggest a functional role of PARP-2 activity in the maintenance of telomere integrity.

* Corresponding author. Mailing address: UPR 9003 du CNRS, Ecole Supérieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, BP10413, F-67412 Illkirch, France. Phone: (33) 390 24 47 04. Fax: (33) 390 24 46 86. E-mail: schreibe{at}esbs.u-strasbg.fr.

{dagger} F.D., M.-J.G.-P., and I.J. contributed equally to this work.

Molecular and Cellular Biology, February 2004, p. 1595-1607, Vol. 24, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.4.1595-1607.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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