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Chromosome end maintenance by telomerase.

ABSTRACT: Telomeres, protein-DNA complexes at the ends of eukaryotic linear chromosomes, are essential for genome stability. The accumulation of chromosomal abnormalities in the absence of proper telomere function is implicated in human aging and cancer. Repetitive telomeric sequences are maintained by telomerase, a ribonucleoprotein complex containing a reverse transcriptase subunit, a template RNA, and accessory components. Telomere elongation is regulated at multiple levels, including assembly of the telomerase holoenzyme, recruitment of telomerase to the chromosome terminus, and telomere accessibility. This minireview provides an overview of telomerase structure, function, and regulation and the role of telomerase in human disease.

SUBMITTER: Osterhage JL

PROVIDER: S-EPMC2713563 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Chromosome end maintenance by telomerase.

Osterhage Jennifer L JL Friedman Katherine L KL

The Journal of biological chemistry 20090312 24

Telomeres, protein-DNA complexes at the ends of eukaryotic linear chromosomes, are essential for genome stability. The accumulation of chromosomal abnormalities in the absence of proper telomere function is implicated in human aging and cancer. Repetitive telomeric sequences are maintained by telomerase, a ribonucleoprotein complex containing a reverse transcriptase subunit, a template RNA, and accessory components. Telomere elongation is regulated at multiple levels, including assembly of the t ...[more]

PMID: 19286666

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SMUG1 promotes telomere maintenance through telomerase RNA end-processing

Project description:Single-strand selective uracil DNA-glycosylase (SMUG1) associates with the DKC1-H/ACA ribonucleoprotein complex, which is essential for telomerase biogenesis. We show herein, that SMUG1 interacts with the telomerase RNA component, hTERC, and is required for co-transcriptional processing of the nascent transcript towards mature hTERC. We demonstrate that SMUG1 regulates the presence of base modifications between the CR4/CR5 region and the H-box situated towards the 3´-end of hTERC. Increased levels of hTERC base modifications are accompanied by reduced DKC1 binding. Loss of SMUG1 leads to an imbalance between mature hTERC and its processing intermediates, leading to the accumulation of 3´-polyadenylated and 3´-extended intermediates that are degraded in an EXOSC10-independent RNA degradation pathway. Consequently, SMUG1-deprived cells, present telomerase deficiency leading to impaired bone marrow proliferation in SMUG1-knockout mice.

2019-08-11 | GSE116580 | GEO

Telomerase structures and regulation: shedding light on the chromosome end.

Project description:During genome replication, telomerase adds repeats to the ends of chromosomes to balance the loss of telomeric DNA. The regulation of telomerase activity is of medical relevance, as it has been implicated in human diseases such as cancer, as well as in aging. Until recently, structural information on this enzyme that would facilitate its clinical manipulation had been lacking due to telomerase very low abundance in cells. Recent cryo-EM structures of both the human and Tetrahymena thermophila telomerases have provided a picture of both the shared catalytic core of telomerase and its interaction with species-specific factors that play different roles in telomerase RNP assembly and function. We discuss also progress toward an understanding of telomerase RNP biogenesis and telomere recruitment from recent studies.

| S-EPMC8240480 | biostudies-literature

TPP1 OB-fold domain controls telomere maintenance by recruiting telomerase to chromosome ends.

Project description:Telomere synthesis in cancer cells and stem cells involves trafficking of telomerase to Cajal bodies, and telomerase is thought to be recruited to telomeres through interactions with telomere-binding proteins. Here, we show that the OB-fold domain of the telomere-binding protein TPP1 recruits telomerase to telomeres through an association with the telomerase reverse transcriptase TERT. When tethered away from telomeres and other telomere-binding proteins, the TPP1 OB-fold domain is sufficient to recruit telomerase to a heterologous chromatin locus. Expression of a minimal TPP1 OB-fold inhibits telomere maintenance by blocking access of telomerase to its cognate binding site at telomeres. We identify amino acids required for the TPP1-telomerase interaction, including specific loop residues within the TPP1 OB-fold domain and individual residues within TERT, some of which are mutated in a subset of pulmonary fibrosis patients. These data define a potential interface for telomerase-TPP1 interaction required for telomere maintenance and implicate defective telomerase recruitment in telomerase-related disease.

| S-EPMC3516183 | biostudies-literature

SMUG1 promotes telomere maintenance through telomerase RNA end-processing

Project description:SMUG1 promotes telomere maintenance through telomerase RNA end-processing

| PRJNA479447 | ENA

Involvement of telomerase reverse transcriptase in heterochromatin maintenance.

Project description:In the fission yeast Schizosaccharomyces pombe, centromeric heterochromatin is maintained by an RNA-directed RNA polymerase complex (RDRC) and the RNA-induced transcriptional silencing (RITS) complex in a manner that depends on the generation of short interfering RNA. In association with the telomerase RNA component (TERC), the telomerase reverse transcriptase (TERT) forms telomerase and counteracts telomere attrition, and without TERC, TERT has been implicated in the regulation of heterochromatin at locations distinct from telomeres. Here, we describe a complex composed of human TERT (hTERT), Brahma-related gene 1 (BRG1), and nucleostemin (NS) that contributes to heterochromatin maintenance at centromeres and transposons. This complex produced double-stranded RNAs homologous to centromeric alpha-satellite (alphoid) repeat elements and transposons that were processed into small interfering RNAs targeted to these heterochromatic regions. These small interfering RNAs promoted heterochromatin assembly and mitotic progression in a manner dependent on the RNA interference machinery. These observations implicate the hTERT/BRG1/NS (TBN) complex in heterochromatin assembly at particular sites in the mammalian genome.

| S-EPMC3993606 | biostudies-literature

Finding the end: recruitment of telomerase to telomeres.

Project description:Telomeres, the ends of linear eukaryotic chromosomes, are characterized by the presence of multiple repeats of a short DNA sequence. This telomeric DNA is protected from illicit repair by telomere-associated proteins, which in mammals form the shelterin complex. Replicative polymerases are unable to synthesize DNA at the extreme ends of chromosomes, but in unicellular eukaryotes such as yeast and in mammalian germ cells and stem cells, telomere length is maintained by a ribonucleoprotein enzyme known as telomerase. Recent work has provided insights into the mechanisms of telomerase recruitment to telomeres, highlighting the contribution of telomere-associated proteins, including TPP1 in humans, Ccq1 in Schizosaccharomyces pombe and Cdc13 and Ku70-Ku80 in Saccharomyces cerevisiae.

| S-EPMC3805138 | biostudies-literature

TGS1 mediates 2,2,7-trimethyl guanosine capping of the human telomerase RNA to direct telomerase dependent telomere maintenance.

Project description:Pathways that direct the selection of the telomerase-dependent or recombination-based, alternative lengthening of telomere (ALT) maintenance pathway in cancer cells are poorly understood. Using human lung cancer cells and tumor organoids we show that formation of the 2,2,7-trimethylguanosine (TMG) cap structure at the human telomerase RNA 5' end by the Trimethylguanosine Synthase 1 (TGS1) is central for recruiting telomerase to telomeres and engaging Cajal bodies in telomere maintenance. TGS1 depletion or inhibition by the natural nucleoside sinefungin impairs telomerase recruitment to telomeres leading to Exonuclease 1 mediated generation of telomere 3' end protrusions that engage in RAD51-dependent, homology directed recombination and the activation of key features of the ALT pathway. This indicates a critical role for 2,2,7-TMG capping of the RNA component of human telomerase (hTR) in enforcing telomerase-dependent telomere maintenance to restrict the formation of telomeric substrates conductive to ALT. Our work introduces a targetable pathway of telomere maintenance that holds relevance for telomere-related diseases such as cancer and aging.

| S-EPMC9050681 | biostudies-literature

Human sarcomas are mosaic for telomerase-dependent and telomerase-independent telomere maintenance mechanisms: implications for telomere-based therapies.

Project description:Telomere shortening necessitates that tumor cells activate a telomere maintenance mechanism (TMM) to support immortalization. Although most tumor cells activate expression of the enzyme telomerase, some cells elongate telomeres in a telomerase-independent manner, termed alternative lengthening of telomeres (ALT). Previous studies have evaluated the presence of telomerase or ALT mechanisms or both in a variety of tumor types. Our studies also show that TMMs are not mutually exclusive in some tumors. In contrast, our IHC analyses of human sarcomas identified a subset of tumors with some cells containing ALT-associated PML bodies, a hallmark of ALT, and separate cells expressing telomerase in the same tumor. By using a second set of human osteosarcomas, we merged IHC and biochemical analyses to characterize more fully the tumor TMM. The IHC data reveal the presence of both telomerase- and ALT-positive tumor cells in samples that demonstrate characteristics of both telomerase and ALT in biochemical assays. These assays, which measure telomere length and telomerase activity of tumor extracts, are conventionally used to classify tumor TMM. Our results suggest that TMM is not a single or perhaps static characteristic of some tumors and that TMM heterogeneity should be considered in tumor stratification. Furthermore, clinical interest in telomere-based therapies may necessitate accurate characterization of tumor TMM before treatment to maximize therapeutic efficacy.

| S-EPMC3532709 | biostudies-literature

Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita.

Project description:Dyskeratosis congenita (DC) patients suffer a progressive and ultimately fatal loss of hematopoietic renewal correlating with critically short telomeres. The predominant X-linked form of DC results from substitutions in dyskerin, a protein required both for ribosomal RNA (rRNA) pseudouridine modification and for cellular accumulation of telomerase RNA (TER). Accordingly, alternative models have posited that the exhaustion of cellular renewal in X-linked DC arises as a primary consequence of ribosome deficiency or telomerase deficiency. Here we test, for the first time, whether X-linked DC patient cells are compromised for telomerase function at telomeres. We show that telomerase activation in family-matched control cells allows telomere elongation and telomere length maintenance, while telomerase activation in X-linked DC patient cells fails to prevent telomere erosion with proliferation. Furthermore, we demonstrate by phenotypic rescue that telomere defects in X-linked DC patient cells arise solely from reduced accumulation of TER. We also show that X-linked DC patient cells averted from premature senescence support normal levels of rRNA pseudouridine modification and normal kinetics of rRNA precursor processing, in contrast with phenotypes reported for a proposed mouse model of the human disease. These findings support the significance of telomerase deficiency in the pathology of X-linked DC.

| S-EPMC1619937 | biostudies-literature

Chromosome End Diversification in Sciarid Flies.

Project description:BackgroundDipterans exhibit a remarkable diversity of chromosome end structures in contrast to the conserved system defined by telomerase and short repeats. Within dipteran families, structure of chromosome termini is usually conserved within genera. With the aim to assess whether or not the evolutionary distance between genera implies chromosome end diversification, this report exploits two representatives of Sciaridae, Rhynchosciara americana, and Trichomegalosphyspubescens.MethodsProbes and plasmid microlibraries obtained by chromosome end microdissection, in situ hybridization, cloning, and sequencing are among the methodological approaches employed in this work.ResultsThe data argue for the existence of either specific terminal DNA sequences for each chromosome tip in T. pubescens, or sequences common to all chromosome ends but their extension does not allow detection by in situ hybridization. Both sciarid species share terminal sequences that are significantly underrepresented in chromosome ends of T. pubescens.ConclusionsThe data suggest an unusual terminal structure in T. pubescens chromosomes compared to other dipterans investigated. A putative, evolutionary process of repetitive DNA expansion that acted differentially to shape chromosome ends of the two flies is also discussed.

| S-EPMC7694509 | biostudies-literature

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