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Par-4 Binds to Topoisomerase 1 and Attenuates Its DNA Relaxation Activity

Departments of ¹ Radiation Medicine and ² Microbiology, Immunology, and Molecular Genetics, ³ Graduate Center for Toxicology, and ⁴ Markey Cancer Center, University of Kentucky, Lexington, Kentucky; and ⁵ Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Vivek M. Rangnekar, Department of Radiation Medicine, University of Kentucky, Combs Research Building, Room 309, 800 Rose Street, Lexington, KY 40536. Phone: 859-257-2677; Fax: 859-257-9608; E-mail: vmrang01{at}email.uky.edu.

Key Words: Par-4 • topoisomerase 1 • DNA relaxation • cellular transformation

The regulation of DNA relaxation by topoisomerase 1 (TOP1) is essential for DNA replication, transcription, and recombination events. TOP1 activity is elevated in cancer cells, yet the regulatory mechanism restraining its activity is not understood. We present evidence that the tumor suppressor protein prostate apoptosis response-4 (Par-4) directly binds to TOP1 and attenuates its DNA relaxation activity. Unlike camptothecin, which binds at the TOP1-DNA interface to form cleavage complexes, Par-4 interacts with TOP1 via its leucine zipper domain and sequesters TOP1 from the DNA. Par-4 knockdown by RNA interference enhances DNA relaxation and gene transcription activities and promotes cellular transformation in a TOP1-dependent manner. Conversely, attenuation of TOP1 activity either by RNA interference or Par-4 overexpression impedes DNA relaxation, cell cycle progression, and gene transcription activities and inhibits transformation. Collectively, our findings suggest that Par-4 serves as an intracellular repressor of TOP1 catalytic activity and regulates DNA topology to suppress cellular transformation. [Cancer Res 2008;68(15):6190–8]