Human telomerase holoenzyme consists of the catalytic component TERT and the template RNA TERC. However, a network of accessory proteins play key roles in assembly, localization and stability of the holoenzyme. In the very last years, increasing evidence highlighted a role of different components of the RNAi machinery in the regulation of telomerase activity, adding a new layer of complexity to the mechanisms regulating human telomerase activity. Recently, we have shown that genetic impairment of AGO2 results into telomere shortening, impairment of TERT/TERC association and decrease of telomerase activity.
We aim to further characterize the molecular machinery mediating the effect exerted by AGO2 on telomerase assembly by a combination of biochemical and molecular approaches in human cell lines.
Defects in genes involved in telomerase biology affect the renewal of critical stem cell populations and cause disorders such as telomeropathies. Moreover, aberrant activation of telomerase in somatic cells allows neoplastic cells to proliferate indefinitely, thus contributing to tumorigenesis. For these reasons, identification of new players involved in telomerase regulation is crucial for the determination of novel therapeutic targets and biomarkers.
In order to attain appropriate telomerase activity, both TERT and TERC expression are required. Furthermore assembly of the telomerase holoenzyme requires a plethora of enzymes and RNA-binding proteins that finely controlled processing, stability and activity of TERC. Fulfilment of these requirements provides several opportunities to fine tune telomerase activity in the cell. Indeed, great strides have been made in recent years to increase our knowledge of how telomerase is assembled and to identify new players in telomerase regulation. Interestingly, rapidly emerging scientific findings suggest an unexpected function of components of the RNAi machinery in TERC processing and activity.
In this scenario new sRNAs originating from TERC and novel TERC-binding proteins (AGO2, FXR1, RHAU and HuR) have been described. Since abnormal expression of other well-known telomerase accessory proteins (i.e. DCK1, NOP10, TCAB1, PARN) are linked to tumorigenesis and telomere disease, the possible deregulation of RNAi machinery in these pathological contextes deserves further investigations. These efforts will contribute not only to our understanding of natural cellular processes, but also offer new possibilities for the development of novel therapeutic targets and biomarkers in a wide range of pathologies.
Financing my project Sapienza will give me the opportunity to collect fundamental data which will represent the basis for a wider research project aimed at shedding light on this intriguing function of AGO2 in the context of telomerase biology.