A key question in the field of RNA regulation is how some exosome substrates, such as spliceosomal snRNAs and telomerase RNA, evade degradation and are processed into stable, functional RNA molecules. Typical feature of these non-coding RNAs is presence of the Sm complex at the 3'end of the mature RNA molecule. Here, we report that in Saccharomyces cerevisiae presence of intact Sm binding site is required for the exosome-mediated processing of telomerase RNA from a polyadenylated precursor into its mature form and is essential for its function in elongating telomeres. Additionally, we demonstrate that the same pathway is involved in the maturation of snRNAs. Furthermore, the insertion of an Sm binding site into an unstable RNA that is normally completely destroyed by the exosome, leads to its partial stabilization. We also show that telomerase RNA accumulates in Schizosaccharomyces pombe exosome mutants, suggesting a conserved role for the exosome in processing and degradation of telomerase RNA. In summary, our data provide important mechanistic insight into the regulation of exosome dependent RNA processing as well as telomerase RNA biogenesis.
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Mol Biol Rep
January 2025
Department of Integrative Biology, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
Telomerase, constituted by the dynamic duo of telomerase reverse transcriptase (TERT), the catalytic entity, and an integral RNA component (TERC), is predominantly suppressed in differentiated human cells due to postnatal transcriptional repression of the TERT gene. Dysregulation of telomerase significantly contributes to cancer development via telomere-dependent and independent mechanisms. Telomerase activity is often elevated in advanced cancers, with TERT reactivation and upregulation of TERC observed in early tumorigenesis.
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January 2025
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA.
Biogenesis of human telomerase requires its RNA subunit (hTR) to fold into a multi-domain architecture that includes the template-pseudoknot (t/PK) and the three-way junction (CR4/5). These hTR domains bind the telomerase reverse transcriptase (hTERT) protein and are essential for telomerase activity. Here, we probe hTR structure in living cells using dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) and ensemble deconvolution analysis.
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January 2025
Department of Pediatrics, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome, rarely associated with bone marrow failure (BMF). Telomere biology disorders (TBD) are caused by inherited defects in telomerase processes and can have heterogeneous presentations including idiopathic pulmonary fibrosis, cirrhosis, and BMF. We report a case of a 10-year-old male from Lima, Peru, who presented with HLH as the initial manifestation of a TBD.
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February 2025
Department of Chemical and Biological Sciences, Biosciences Institute, São Paulo State University (UNESP), Botucatu, SP, Brazil.
Leishmaniasis is a neglected tropical disease caused by protozoans of the Leishmania genus, against which no effective treatment or control is available. Like other eukaryotes, parasite telomeres are maintained by telomerase, a ribonucleoprotein complex vital for genome stability. Its protein component, TERT (telomerase reverse transcriptase), presents four structural and functional domains, with the TEN (Telomerase N-terminal) and TRBD (Telomerase RNA-binding) located at its N-terminal.
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December 2024
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China.
Increased telomerase activity has been considered as a conspicuous sign of human cancers. The catalytic cores of telomerase involve a reverse transcriptase and the human telomerase RNA (hTR). However, current detection of telomerase is largely limited to its activity at the tissue and single-cell levels.
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