Abstract
The nucleolar protein dyskerin is involved in the modification of specific uridine residues to pseudouridine on ribosomal and small nuclear RNAs and in the stabilization of the telomerase RNA component (TERC). In this study we investigated for the first time the relationship between dyskerin expression and telomerase activity in a series of 61 primary breast carcinomas. We found that when dyskerin mRNA values were very low the telomerase activity was markedly reduced, independently of the expression of other important components of the telomerase complex such as telomerase reverse transcriptase (TERT). In vitro experiments showed that reduction of dyskerin expression affect telomerase activity through the reduction of TERC. Only when TERC levels were strongly reduced telomerase activity was hindered. Retroviral mediated over-expression of TERC abolished the telomerase impairment due to dyskerin knock down. In conclusion, our results indicated that, beside its effect on ribosome biogenesis, the levels of dyskerin in cancer cells modulate telomerase activity through the regulation of TERC levels, independently of TERT expression. This should be taken into consideration when utilizing TERT expression as a surrogate indicator of telomerase activity in tumour pathology.
Highlights
Mutation of the DKC1 gene causes the rare skin, mucosal and bone marrow failure syndrome termed X-linked dyskeratosis congenita (DC) [1]
The relationship between dyskerin expression and telomerase activity was evaluated in a series of human breast carcinomas
Telomerase activity in cancer cells is highly variable and in most cases directly linked to the expression of telomerase reverse transcriptase (TERT), which is commonly considered the limiting component of the telomerase complex [10,18,19,20,21]
Summary
Mutation of the DKC1 gene causes the rare skin, mucosal and bone marrow failure syndrome termed X-linked dyskeratosis congenita (DC) [1]. On the one hand it binds to a group of small nucleolar RNAs (snoRNAs) and of small Cajal body-specific RNAs (scaRNAs) containing sequence elements termed H/ACA [2]. Increased cancer susceptibility has been observed in the DKC1 hypomorphic mouse, in which dyskerin expression is reduced by means of gene targeting to approximately 30% of normal levels [6,7]. These observations indicate that, at least in DC patients and in DKC1 hypomorphic mice, dyskerin may behave as a tumour suppressor, prompting cancer when not functioning properly [8]
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