BCCIP is required for the nuclear localization of the p21 protein

The p21 (CDKN1A, Waf1 or Cip1) protein is widely known as an inhibitor of cyclin-dependent kinase (CDK), which plays a critical role in regulation of the G(1)-S transition during the cell cycle progression. The inhibition of G(1)-S transition by p21 is mainly mediated in the nucleus. However, the cytoplasmic p21 has been shown to play a pro-proliferation and anti-apoptosis role. Thus, the regulation of p21's intracellular distribution has a significant implication for cell fate determination. BCCIP is a BRCA2 and CDKN1A Interacting Protein. Previous reports showed that BCCIP enhances the p21 suppression activity towards CDK2, and BCCIP downregulation reduces p21 expression by abrogating p53 transcription activity. In this report, we demonstrate that the BCCIP-p21 interaction is enhanced in response to DNA damage using Fluorescent Resonance Energy Transfer (FRET) technique. We found that the downregulation of BCCIP reduces nuclear p21 and increases cytoplasmic p21. This p21 redistribution is not caused by the reduced expression of endogenous p21 resulting from BCCIP downregulation, because exogenously expressed p21 also preferably distributes in the cytoplasm. The BCCIP regulation of p21 distribution is not related to the status of Thr-145 phosphorylation that is known to cause cytoplasmic distribution. These data suggest that regulation of p21 intracellular distribution as a new mechanism for BCCIP to modulate p21 functions.