The PinX1/NPM interaction associates with hTERT in early-S phase and facilitates telomerase activation

Abstract

Background: Telomere maintenance is an important factor in tumorigenesis. PinX1 is a potent telomerase regulator which also involves in telomerase loading to telomeres. Nucleophosmin (NPM) can partially attenuate PinX1 inhibition of telomerase activity and NPM loading to hTERT requires PinX1. However, the role of the PinX1/NPM interaction in telomerase activity is not fully understood. Method: The long-term effects of PinX1 and NPM down-regulation on telomere length were investigated by TRF assay. The localization of the PinX1/NPM association and the NPM/PinX1/hTERT complex formation were examined by immunofluorescence studies. Results: Concurrent long-term down-regulation of PinX1 and NPM led to a substantial decrease in telomere length. The interaction with PinX1 was crucial in NPM localization in the nucleolus during the S phase. PinX1 and NPM associated throughout S phase and the NPM/PinX1/hTERT complex formation peaked during the early-S phase. The PinX1/NPM interaction was shown to localize away from Cajal Bodies at the start of S phase. Conclusion: PinX1/NPM interaction is important in telomerase regulation during catalysis. NPM is recruited to hTERT by PinX1 and is required in the proposed telomerase modulating unit to activate telomerase when telomere extension occurs during S phase.