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, Viatcheslav A. Soldatenkov

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Abstract

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. K0.5 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.

Original languageEnglish (US)
Pages (from-to)17076-17083
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number17
DOIs
StatePublished - Apr 29 2005

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lonskaya, I., Potaman, V. N., Shlyakhtenko, L. S., Oussatcheva, E. A., Lyubchenko, Y. L., & Soldatenkov, V. A. (2005). Regulation of poly(ADP-ribose) polymerase-1 by DNA structure-specific binding. Journal of Biological Chemistry, 280(17), 17076-17083. https://doi.org/10.1074/jbc.M413483200