Telomerase activation and telomere maintenance are critical for cellular immortalization and transformation. PIN2/TERF1-interacting telomerase inhibitor 1 (PinX1) is a telomerase regulator and the aberrant expression of PinX1 causes telomere shortening. Identifying PinX1-interacting proteins is important for understanding telomere maintenance. We found that PinX1 directly interacts with nucleophosmin (NPM), a protein that has been shown to positively correlate with telomerase activity. We further showed that PinX1 acts as a linker in the association between NPM and hTERT, the catalytic subunit of telomerase. Additionally, the recruitment of NPM by PinX1 to the telomerase complex could partially attenuate the PinX1-mediated inhibition on telomerase activity. Taken together, our data reveal a novel mechanism that regulates telomerase activation through the interaction between NPM, PinX1 and the telomerase complex.

Based on the structural scaffolds of natural products, two series of flavonoid derivatives, for a total of twelve compounds, were designed and synthesized as potential human telomerase inhibitors. Using a modified TRAP-PCR assay, compound 5c exhibited the most potent inhibitory activity against human telomerase with an IC50 value of less than 50 μM. In vitro, the results demonstrated that compound 5c had potent anticancer activity against five classes of tumor cell lines. The molecular docking and molecular dynamics analyses binding to the human telomerase holoenzyme were performed to elucidate the binding mode of active compound 5c. This finding helps the rational design of more potent telomerase inhibitors based on the structural scaffolds of natural products.

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. Electronic supplementary material The online version of this article (10.1186/s13578-019-0306-y) contains supplementary material, which is available to authorized users.