Abstract
Telomerase consists of the catalytic protein TERT and the RNA TERC. Mutations in TERC are linked to human diseases, but the underlying mechanisms are poorly understood. Here we report that the RNA-binding protein HuR associates with TERC and promotes the assembly of the TERC/TERT complex by facilitating TERC C106 methylation. Dyskeratosis congenita (DC)-related TERC U100A mutation impair the association of HuR with TERC, thereby reducing C106 methylation. Two other TERC mutations linked to aplastic anemia and autosomal dominant DC, G107U, and GC107/108AG, likewise disrupt methylation at C106. Loss-of-HuR binding and hence lower TERC methylation leads to decreased telomerase activity and telomere shortening. Furthermore, HuR deficiency or mutation of mTERC HuR binding or methylation sites impair the renewal of mouse hematopoietic stem cells, recapitulating the bone marrow failure seen in DC. Collectively, our findings reveal a novel function of HuR, linking HuR to telomerase function and TERC-associated DC.
Highlights
The majority of human cancer cells and germ line cells express telomerase, a ribonucleoprotein with reverse transcriptase activity that adds telomeric DNA repeats to the end of telomeres
The regulation of telomerase activity by HuR was found to impact on the renewal of hematopoietic stem cells (HSCs) and was linked to dyskeratosis congenita, aplastic anemia, and autosomal dominant dyskeratosis congenita
TERC UUUUU and GUUUUUC are the major motifs for HuR binding. These results suggest that the association of HuR with TERC may be linked to dyskeratosis congenita (DC), since U100A is a DC-related mutation[4]
Summary
The majority of human cancer cells and germ line cells express telomerase, a ribonucleoprotein with reverse transcriptase activity that adds telomeric DNA repeats to the end of telomeres. Telomerase dysfunction caused by human TERC mutations is linked to numerous human diseases, including pulmonary fibrosis, human cancer, and premature aging syndromes, such as dyskeratosis congenita (DC) and aplastic anemia[1,4,5,6]. M6A is the predominant methylation site[13], m5C is widely identified in human coding and non-coding RNAs9,10. HuR [human antigen R, known as ELAVL1 (embryonic lethal abnormal vision-like 1)], the ubiquitously expressed member of Hu/ELAV RNA-binding protein family, has been described to regulate the post-transcriptional fate of a number of coding and non-coding RNAs24–26, thereby regulating many cell activities (proliferation, survival, apoptosis, senescence, and differentiation) and affecting. The regulation of telomerase activity by HuR was found to impact on the renewal of hematopoietic stem cells (HSCs) and was linked to dyskeratosis congenita, aplastic anemia, and autosomal dominant dyskeratosis congenita
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