Adding to the ends: what makes telomerase processive and how important is it?

Lue, Neal F.

doi:10.1002/bies.20093

Cited by 72 publications

(68 citation statements)

References 94 publications

(112 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Together, TER and TERT provide the minimal telomerase subunits required to reconstitute enzymatic activity in vitro (Kelleher et al 2002). Telomerase synthesizes telomeric repeats (TTGGGG in Tetrahymena) by processive nucleotide addition across the template to generate a single repeat (nucleotide addition processivity, NAP) and processive repeat addition by reuse of the same template (repeat addition processivity, RAP) (Greider and Blackburn 1989;Greider 1991;Lue 2004). The endogenously assembled telomerase holoenzymes contain additional protein subunits essential for activity in vivo, whose roles in RNP assembly, stabilization, and localization have been less well defined (Harrington 2003;Chen and Greider 2004).…”

Section: Introductionmentioning

confidence: 99%

Structural study of elements of Tetrahymena telomerase RNA stem–loop IV domain important for function

Richards¹,

Wu²,

Trantı́rek³

et al. 2006

RNA

View full text Add to dashboard Cite

Tetrahymena telomerase RNA (TER) contains several regions in addition to the template that are important for function. Central among these is the stem-loop IV domain, which is involved in both catalysis and RNP assembly, and includes binding sites for both the holoenzyme assembly protein p65 and telomerase reverse transcriptase (TERT). Stem-loop IV contains two regions with high evolutionary sequence conservation: a central GA bulge between helices, and a terminal loop. We solved the solution structure of loop IV and modeled the structure of the helical region containing the GA bulge, using NMR and residual dipolar couplings. The central GA bulge with flanking C-G base pairs induces a ;50°semi-rigid bend in the helix. Loop IV is highly structured, and contains a conserved C-U base pair at the top of the helical stem. Analysis of new and previous biochemical data in light of the structure provides a rationale for some of the sequence conservation in this region of TER. The results suggest that during holoenzyme assembly the protein p65 recognizes a bend in stem IV, and this binding to central stem IV helps to position the structured loop IV for interaction with TERT and other region(s) of TER.

show abstract

Section: Introductionmentioning

confidence: 99%

Structural study of elements of Tetrahymena telomerase RNA stem–loop IV domain important for function

Richards¹,

Wu²,

Trantı́rek³

et al. 2006

RNA

View full text Add to dashboard Cite

show abstract

“…Mutational analysis indicates that these motifs are likely to mediate binding to telomeric DNA and telomerase RNA. Direct recognition of telomeric DNA by TERT is believed to be sequence-dependent and to allow telomerase to catalyze the addition of multiple repeats without dissociation from the DNA (13,14).In unicellular organisms, telomerase is constitutively active and required for the long-term proliferation of cells. In some multicellular organisms, including humans, telomerase is repressed in normal somatic tissues but activated in cancer cells, and is believed to promote tumor growth (15).…”

mentioning

confidence: 99%

“…Thus, the RNA subunit serves multiple essential roles in the course of a normal telomerase reaction. The TERT protein is well conserved in evolution and comprises a central RT domain that is flanked on both the N-and C-terminal side by telomerase-specific motifs (4,12,13). Mutational analysis indicates that these motifs are likely to mediate binding to telomeric DNA and telomerase RNA.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Telomerase can act as a template- and RNA-independent terminal transferase

Lue

Bosoy

Moriarty

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Telomerase is a special reverse transcriptase that extends one strand of the telomere repeat by using a template embedded in an RNA subunit. Like other polymerases, telomerase is believed to use a pair of divalent metal ions (coordinated by a triad of aspartic acid residues) for catalyzing nucleotide addition. Here we show that, in the presence of manganese, both yeast and human telomerase can switch to a template-and RNA-independent mode of DNA synthesis, acting in effect as a terminal transferase. Even as a terminal transferase, yeast telomerase retains a species-dependent preference for GT-rich, telomere-like DNA on the 5 end of the substrate. The terminal transferase activity of telomerase may account for some of the hitherto unexplained effects of telomerase overexpression on cell physiology.reverse transcriptase ͉ telomere ͉ divalent metal ion T elomerase is a ribonucleoprotein responsible for the synthesis of one strand of the telomere terminal repeat. The catalytic core of telomerase consists minimally of two components: an RNA in which the template is embedded (named TLC1 in the budding yeast Saccharomyces cerevisiae), and a reverse transcriptase (RT)-like protein that mediates catalysis (named TERT in general and Est2p in yeast) (1-4). Telomerase RNAs from different organisms are divergent in sequence but share conserved secondary structural elements (5, 6). Many mutations in nontemplate regions of telomerase RNA reduced enzyme activity, suggesting that these regions contribute important catalytic functions [although the precise nature of the contribution(s) is not clear] (7-9). Other RNA structures act to define the boundary of the template segment that supports reverse transcription (10, 11). Thus, the RNA subunit serves multiple essential roles in the course of a normal telomerase reaction. The TERT protein is well conserved in evolution and comprises a central RT domain that is flanked on both the N-and C-terminal side by telomerase-specific motifs (4, 12, 13). Mutational analysis indicates that these motifs are likely to mediate binding to telomeric DNA and telomerase RNA. Direct recognition of telomeric DNA by TERT is believed to be sequence-dependent and to allow telomerase to catalyze the addition of multiple repeats without dissociation from the DNA (13,14).In unicellular organisms, telomerase is constitutively active and required for the long-term proliferation of cells. In some multicellular organisms, including humans, telomerase is repressed in normal somatic tissues but activated in cancer cells, and is believed to promote tumor growth (15). Although the two core components of telomerase are generally assumed to act in concert to replenish telomeres, there is increasing evidence that the TERT protein can have physiologic effects that are independent of telomere length and telomerase . For instance, in mice, TERT overexpression in the absence of telomerase RNA was reported to have an inhibitory effect on tumorigenesis and wound healing (20). The mechanisms for such effects are currently no...

show abstract

“…The genes of these, mostly brain-specific, RNAs are subject to genomic imprinting. Vertebrate telomerase [260], finally, contains a conserved H/ACA box snoRNA domain [284,58].…”

Section: Small Nucleolar Rnas (Snornas)mentioning

confidence: 99%

Evolutionary patterns of non-coding RNAs

Bompfünewerer

Flamm

Fried

et al. 2005

Theory in Biosciences

View full text Add to dashboard Cite

A plethora of new functions of non-coding RNAs have been discovered in past few years. In fact, RNA is emerging as the central player in cellular regulation, taking on active roles in multiple regulatory layers from transcription, RNA maturation, and Manuscript January 2005RNA modification to translational regulation. Nevertheless, very little is known about the evolution of this "Modern RNA World" and its components. In this contribution we attempt to provide at least a cursory overview of the diversity of non-coding RNAs and functional RNA motifs in non-translated regions of regular messenger RNAs (mRNAs) with an emphasis on evolutionary questions. This survey is complemented by an in-depth analysis of examples from different classes of RNAs focusing mostly on their evolution in the vertebrate lineage. We present a survey of Y RNA genes in vertebrates, studies of the molecular evolution of the U7 snRNA, the snoRNAs E1/U17, E2, and E3, the Y RNA family, the let-7 microRNA family, and the mRNA-like evf-1 gene. We furthermore discuss the statistical distribution of microRNAs in metazoans, which suggests an explosive increase in the microRNA repertoire in vertebrates. The analysis of the transcription of non-coding RNAs (ncRNAs) suggests that small RNAs in general are genetically mobile in the sense that their association with a hostgene (e.g. when transcribed from introns of a mRNA) can change on evolutionary time scales. The let-7 family demonstrates, that even the mode of transcription (as intron or as exon) can change among paralogous ncRNA.

show abstract

Adding to the ends: what makes telomerase processive and how important is it?

Cited by 72 publications

References 94 publications

Structural study of elements of Tetrahymena telomerase RNA stem–loop IV domain important for function

Structural study of elements of Tetrahymena telomerase RNA stem–loop IV domain important for function

Telomerase can act as a template- and RNA-independent terminal transferase

Evolutionary patterns of non-coding RNAs

Contact Info

Product

Resources

About