Par-4 binds to topoisomerase 1 and attenuates its DNA relaxation activity

The regulation of DNA relaxation by topoisomerase 1 (TOP1) is essential for DNA replication, transcription, and recombination events. TOPI 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 TOPI and attenuates its DNA relaxation activity. Unlike camptothecin, which binds at the TOPI-DNA interface to form cleavage complexes, Par-4 interacts with TOPI via its leucine zipper domain and sequesters TOPI from the DNA. Par-4 knockdown by RNA interference enhances DNA relaxation and gene transcription activities and promotes cellular transformation in a TOPI-dependent manner. Conversely, attenuation of TOPI activity either by RNA interference or Par-4 overexpression impedes DNA relaxation, cell cycle progression, and gene transcription activities and inhibits transformation. Colleclively, our findings suggest that Par-4 serves as an intracellular repressor of TOPI catalytic activity and regulates DNA topology to suppress cellular transformation.