Human Telomerase RNA: Telomerase Component or More?

Abstract

Telomerase is a ribonucleoprotein complex that maintains the lengths of telomeres. Most studies of telomerase function have focused on the involvement of telomerase activation in the immortalization of cancer cells and cellular rejuvenation. However, some studies demonstrated that the results do not meet expectations for telomerase action in telomere maintenance. Recent results give reason to think that major telomerase components-the reverse transcriptase protein subunit and telomerase RNA-may participate in many cellular processes, including the regulation of apoptosis and autophagy, cell survival, pro-proliferative effects, regulation of gene expression, and protection against oxidative stress. However, the difficulties faced by scientist when researching telomerase component functions often reduce confidence in the minor effects observed in experiments. In this review, we focus on the analysis of the functions of telomerase components (paying more attention to the telomerase RNA component), both as a complex and as independent components, providing effects that are not associated with telomerase activity and telomere length maintenance. Despite the fact that the data on alternative roles of telomerase components look illusory, it would be wrong to completely reject the possibility of their involvement in other biological processes excluded from research/discussion. Investigations to improve the understanding of every aspect of the functioning of telomerase components will provide the basis for a more precise development of approaches to regulate cellular homeostasis, which is important for carcinogenesis and aging.

Keywords: alternative function; ribonucleoprotein particles; telomerase; telomere.

Figure 1

Human telomerase structure. (A) Secondary structure of hTERC. (B) Domain architecture of hTERT. (C) Cryo-EM structure of the human telomerase holoenzyme in two views [26] (Adapted with permission from Elsevier). Subunits are colored as labeled.

Figure 2

Multistage process of assembly of the active telomerase complex. Scheme illustrating different stages of telomerase complex assembly and its binding to telomeres.

Figure 3

Catalytic cycle of telomerase. Scheme illustrating the telomerase active cycle and its modulation by TPP1.

Figure 4

Model of hTERC biogenesis, depicting the competition between processing and degradation, and trafficking through cellular organelles with the distribution of functions. Telomerase RNA is synthesized as a long precursor that may be degraded, processed to the mature form following association with hTERT or it may work outside of the telomerase complex. TERC is involved in gene expression regulation due to its interaction with promoter regions of genes involved in the regulation of proliferation and cell cycle progression. TERC is transported from the nucleus to the cytoplasm where it may associate with TERT and be reimported to the nucleus to elongate the telomeric repeats. On the other hand, TERC is imported to the mitochondria where it is processed and reexported to the cytoplasm. The precursor of TERC is translated and the obtained TERP protein protects cells under stressful conditions.