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. 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.
Goswami
Anindya
A
Department of Radiation Medicine, Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536, USA.
Qiu
Shirley
S
Dexheimer
Thomas S
TS
Ranganathan
Padhma
P
Burikhanov
Ravshan
R
Pommier
Yves
Y
Rangnekar
Vivek M
VM
D000818:Animals; D001483:Base Sequence; D002461:Cell Line, Transformed; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D017931:DNA Primers; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D016350:Leucine Zippers; D051379:Mice; D041681:NIH 3T3 Cells; D011485:Protein Binding; D018179:Receptors, Thrombin / Q000378:metabolism*
D017931:DNA Primers; D018179:Receptors, Thrombin; D004247:DNA; D004264:DNA Topoisomerases, Type I; C112908:protease-activated receptor 4