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J. Biol. Chem., Vol. 280, Issue 17, 17076-17083, April 29, 2005

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Regulation of Poly(ADP-ribose) Polymerase-1 by DNA Structure-specific Binding^*

Irina Lonskaya, Vladimir N. Potaman, Luda S. Shlyakhtenko¶, Elena A. Oussatcheva, Yuri L. Lyubchenko¶, and Viatcheslav A. Soldatenkov||

From the Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D. C. 20057, the Institute of Biosciences and Technology, The Texas A&M University System Health Science Center, Houston, Texas 77030, and the ^¶Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198

Poly(ADP-ribose) polymerase-1 (PARP-1) is an intracellular sensor of DNA strand breaks and plays a critical role in cellular responses to DNA damage. In normally functioning cells, PARP-1 enzymatic activity has been linked to the alterations in chromatin structure associated with gene expression. However, the molecular determinants for PARP-1 recruitment to specific sites in chromatin in the absence of DNA strand breaks remain obscure. Using gel shift and enzymatic footprinting assays and atomic force microscopy, we show that PARP-1 recognizes distortions in the DNA helical backbone and that it binds to three- and four-way junctions as well as to stably unpaired regions in double-stranded DNA. PARP-1 interactions with non-B DNA structures are functional and lead to its catalytic activation. DNA hairpins, cruciforms, and stably unpaired regions are all effective co-activators of PARP-1 auto-modification and poly(ADP-ribosyl)ation of histone H1 in the absence of free DNA ends. Enzyme kinetic analyses revealed that the structural features of non-B form DNA co-factors are important for PARP-1 catalysis activated by undamaged DNA. K_0.5 constants for DNA co-factors, which are structurally different in the degree of base pairing and spatial DNA organization, follow the order: cruciform hairpin « loop. DNA structure also influenced the reaction rate; when a hairpin was substituted with a stably unpaired region, the maximum reaction velocity decreased almost 2-fold. These data suggest a link between PARP-1 binding to non-B DNA structures in genome and its function in the dynamics of local modulation of chromatin structure in the normal physiology of the cell.

Received for publication, November 30, 2004 , and in revised form, February 8, 2005.

^* This work was supported in part by National Institutes of Health Grants CA74175-07 and GM62235. 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 a supplemental table.

^|| To whom correspondence should be addressed: Dept. of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Rd., N.W., The Research Bldg., Rm. E-204A, Box 571482, Washington, D. C. 20057-1482. Fax: 202-687-0400; E-mail: soldates{at}georgetown.edu.

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