Expression of functional alternative telomerase RNA component gene in mouse brain and in motor neurons cells protects from oxidative stress

Abstract

Telomerase, a ribonucleoprotein, is highly expressed and active in many tumor cells and types, therefore it is considered to be a target for anti-cancer agents. On the other hand, recent studies demonstrated that activation of telomerase is a potential therapeutic target for age related diseases. Telomerase mainly consists of a catalytic protein subunit with a reverse transcription activity (TERT) and an RNA component (TERC), a long non-coding RNA, which serves as a template for the re-elongation of telomeres by TERT. We previously showed that TERT is highly expressed in distinct neuronal cells of the mouse brain and its expression declined with age. To understand the role of telomerase in non-mitotic, fully differentiated cells such neurons we here examined the expression of the other component, TERC, in mouse brain. Surprisingly, by first using bioinformatics analysis, we identified an alternative TERC gene (alTERC) in the mouse genome. Using further experimental approaches we described the presence of a functional alTERC in the mouse brain and spleen, in cultures of motor neurons- like cells and neuroblastoma tumor cells. The alTERC is similar (87%) to mouse TERC (mTERC) with a deletion of 18 bp in the TERC conserved region 4 (CR4). This alTERC gene is expressed and its product interacts with the endogenous mTERT protein and with an exogenous human TERT protein (hTERT) to form an active enzyme. Overexpression of the alTERC and the mTERC genes, in mouse motor neurons like cells, increased the activity of TERT without affecting its protein level. Under oxidative stress conditions, alTERC significantly increased the survival of motor neurons cells without altering the level of TERT protein or its activity.The results suggest that the expression of the alTERC gene in the mouse brain provides an additional way for regulating telomerase activity under normal and stress conditions and confers protection to neuronal cells from oxidative stress.

Mitochondria, Telomeres and Telomerase Subunits

“…It has now been reported that telomerase-independent functions of TERC do exist. They include inhibition of apoptosis in immune cells, protection of neuron cells from oxidative stress, and enhancement of cellular inflammatory responses (Gazzaniga and Blackburn, 2014; Eitan et al, 2016; Liu et al, 2019). TERT, however, is expressed in most cancer cells, some adult stem cells and some proliferating cells such as human T cells and B cells (Kim et al, 1994; Hiyama et al, 1995).…”

Radiolabeled Oligonucleotides Targeting the RNA Subunit of Telomerase Inhibit Telomerase and Induce DNA Damage in Telomerase-Positive Cancer Cells

“…hTERT can influence tumor development, oncogenesis, and inflammation via NF-kB and Wnt/b-catenin pathways (7). hTR has been shown to protect against apoptosis and oxidative stress (8,9), and to activate DNA-dependent kinase (DNA-PKcs) to phosphorylate hnRNPA1, which is critical for capping telomeres (10,11).…”

Human Telomerase RNA: Telomerase Component or More?

“…The presence of an additional alternative TERC gene in mice was revealed by searching the mouse genome by BLAT [ 64 ]. Alternative TERC (alTERC) showed an 87.9% similarity to mTERC.…”

“…AlTERC is associated with TERT and supports telomerase activity. Overexpression of mTERC and alTERC protects motor neuron cells from oxidative stress [ 64 ]. The survival of cells expressing alTERC increased in comparison with the survival rate of cells with an increased level of canonical mTERC .…”