The proliferating cell nuclear antigen regulates retinoic acid receptor transcriptional activity through direct protein–protein interaction

Retinoic acid receptors (RARs) interact, in a ligand-dependent fashion, with many coregulators that participate in a wide spectrum of biological responses, ranging from embryonic development to cellular growth control. The transactivating function of these ligand-inducible transcription factors reside mainly, but not exclusively, in their ligand-binding domain (AF2), which recruits or dismiss coregulators in a ligand-dependent fashion. However, little is known about AF2-independent function(s) of RARs. We have isolated the proliferating cell nuclear antigen (PCNA) as a repressor of RAR transcriptional activity, able to interact with an AF2-crippled RAR. The N-terminus of PCNA interacts directly with the DNA-binding domain of RAR, and PCNA is recruited to a retinoid-regulated promoter in intact cells. This interaction affects the transcriptional response to retinoic acid in a promoter-specific manner, conferring an unanticipated role to PCNA in transcriptional regulation. Our findings also suggest a role for RAR as a factor coordinating DNA transcription and repair.