ライフサイエンスコーパス: telomerase

1 lease affect the maturation and stability of telomerase.

2 90% of human cancers can aberrantly activate telomerase.

3 tained by a ribonucleoprotein complex called telomerase.

4 ed control circuit for dynamic regulation of telomerase.

5 specific component of all scaRNPs, including telomerase.

6 sensitive POP1 and POP6 alleles affect yeast telomerase.

7 ecent advances in structural models of human telomerase.

8 hinery and participates in the regulation of telomerase, a ribonucleoprotein complex that maintains t

9 Telomerase, a unique reverse transcriptase that specific

10 accurate telomere replication and to permit telomerase access to the 3' end to solve the end-replica

11 nzymes could be reactivated by intracellular telomerase-activating factors (iTAFs) from multiple cell

12 se that THOR hypermethylation is a prevalent telomerase-activating mechanism in cancer that can act i

13 Conversely, the relative lack of telomerase activation and low expression of independent

14 This report also provides direct evidence of telomerase activation in HBECs near senescence when telo

15 that a potential treatment for IPF based on telomerase activation would be of interest not only for

16 (TERT) is usually the limiting component for telomerase activation, numerous studies have measured TE

17 As a consequence of insufficient telomerase activities in prior generations, both mTert (

18 r-CEH constructs do not, consistent with the telomerase activity and in vivo complementation results.

19 ded forms, which was accompanied by impaired telomerase activity and shortened telomeres.

20 01, a specific PAPD5 inhibitor that restored telomerase activity and telomere length in DC patient in

21 nship between mutation status and downstream telomerase activity and telomere length remains convolut

22 Using direct telomerase activity assays, we discovered that TIN2 stim

23 We further show that endogenous telomerase activity cannot overcome telomere dysfunction

24 es (TERT, WRAP53 and MYC) and an independent telomerase activity gene (ZSCAN4).

25 To date, there is no direct evidence of telomerase activity in adult lung epithelial cells, but

26 stages of hematopoietic stem cells, reduced telomerase activity in bone marrow cells, and altered th

27 Telomerase activity in TOE1-deficient cells could be res

28 Genetic lesions that reduce telomerase activity inhibit stem cell replication and ca

29 In contrast, telomerase activity is silenced in most adult somatic ce

30 Telomerase activity is well documented in embryonic stem

31 ropose that the exquisite kinetic control of telomerase activity may play important roles in both cel

32 ncer cells maintain telomere lengths through telomerase activity or by alternative lengthening of tel

33 activation and low expression of independent telomerase activity pathway during cell division may be

34 subsets of HBECs that activate low levels of telomerase activity to maintain short telomeres.

35 Match oligonucleotides inhibited telomerase activity with high potency, which was not obs

36 an enhancer of FL hTERT splicing, increases telomerase activity, and promotes telomere maintenance i

37 tabilize human telomeric GQ (hGQ) to inhibit telomerase activity, or non-telomeric GQs to manipulate

38 and exhibiting active WNT signaling or high telomerase activity, respectively.

39 an ESCs, the engineered mESCs contained high telomerase activity, which was repressed upon their diff

40 o functional improvements in TERC levels and telomerase activity, with concomitant telomere elongatio

41 th telomere elongation in NSE than SE: three telomerase activity-related genes (TERT, WRAP53 and MYC)

42 ate that PTBP1 reduces hTERT FL splicing and telomerase activity.

43 ruitment to telomeres, and the regulation of telomerase activity.

44 erentiated from these mESCs contained little telomerase activity.

45 Here, we tested the effects of human TIN2 on telomerase activity.

46 sential N-terminal (TEN) domain and roles in telomerase activity.

47 ate (5-MeCITP), functions as an inhibitor of telomerase activity.

48 he mechanisms by which cancer cells increase telomerase activity.

49 telomere repeat lengths by using the enzyme telomerase, although there are some cancer cells that us

50 for the male dominance of HBV-related HCCs; telomerase and AR thus may be targets for intervention o

51 merase complex, the cellular localization of telomerase and its recruitment to telomeres, and the reg

52 es in individuals with germline mutations in telomerase and other telomere-maintenance genes.

53 s dual activity by simultaneously inhibiting telomerase and promoting radiation-induced genomic DNA d

54 essential for enhancing the processivity of telomerase and recruiting the enzyme to telomeres.

55 Both reactivation of telomerase and silencing of p53 rescued hepatocyte forma

56 ) harboring clinically relevant mutations in telomerase and subjected them to an in vitro, stage-spec

57 quires proper spatiotemporal coordination of telomerase and telomeres and remains poorly understood a

58 ns, the low cellular abundance of functional telomerase and the difficulties in quantifying its activ

59 e mechanistic underpinnings of telomeres and telomerase and their roles in ageing and disease.

60 Increased levels of telomerase are found in the vast majority of human cance

61 rities for human and Tetrahymena thermophila telomerase as well as the species specificity of human a

62 Human telomerase assays determined a conserved tyrosine steric

63 combination of ensemble and single-molecule telomerase assays, we discovered that GQ folding of the

64 tein (RNP), comprising vault RNA (vtRNA) and telomerase-associated protein 1 (TEP1), is found in many

65 Mutant telomerase-associated proteins TCAB1 and dyskerin and th

66 oth complexes, Pop1, Pop6, and Pop7 are also telomerase-associated.

67 ies suggest that the dynamic distribution of telomerase between CBs and nucleoplasm uniquely impacts

68 disease relevance of each of these steps of telomerase biogenesis.

69 egion in many cancers and recent advances in telomerase biology has led to a renewed interest in targ

70 not impact Est1's ability to associate with telomerase but did result in decreased association of Es

71 Whereas mislocalization of telomerase by mutation of WDR79 leads to critically shor

72 ally shortened telomeres, mislocalization of telomerase by Nopp140 KD leads to gradual extension of t

73 We provide direct evidence that telomerase can add the nucleotide reverse transcriptase

74 e telomere repeats modulates the kinetics of telomerase catalysis and dissociation.

75 ic folding properties of telomere DNA during telomerase catalysis, and provide a detailed characteriz

76 This more complete model of the human telomerase catalytic core illustrates how domains of TER

77 rase, we built a pseudoatomic model of human telomerase catalytic core that accounts for almost all o

78 ngers domain (IFD)-TRAP regions of the human telomerase catalytic protein subunit TERT into the mouse

79 ls using a non-viral vector to transfect the telomerase catalytic subunit (hTERT) and the simian viru

80 nvert the ITS to a functional telomere is by telomerase-catalyzed addition of telomeric repeats with

81 Purified human telomerase catalyzes processive repeat synthesis, which

82 Telomerase catalyzes telomeric DNA synthesis at chromoso

83 sence of variants in other components of the telomerase complex and their impact on clinical outcomes

84 ALKBH5 also modulates telomerase complex assembly and activity.

85 human cells, telomeres are elongated by the telomerase complex that contains the reverse transcripta

86 human TERT, hTR processing, assembly of the telomerase complex, the cellular localization of telomer

87 ed that TOE1 could interact with hTR and the telomerase complex.

88 of nascent product folding within the active telomerase complex.

89 Variants in genes encoding for telomerase components have been associated with a spectr

90 ons in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as th

91 Telomerase contains a catalytic core of telomerase rever

92 In contrast, telomerase continues elongation after inserting oxidized

93 In most eukaryotes, telomerase counteracts chromosome erosion by adding repe

94 tion of these two cell fates during aging of telomerase deficient zebrafish.

95 The growth of telomerase-deficient cancers depends on the alternative

96 Treatment of both wild-type and telomerase-deficient mice with telomerase gene therapy p

97 We also address some of the challenges to telomerase-directed therapies including potential therap

98 t with formation of GQ structures within the telomerase-DNA complex.

99 Thus upregulation of telomerase does not appear to associate with longer telo

100 ncers maintain their telomeres by activating telomerase, driven by the transcriptional upregulation o

101 I to attain the first proof of concept on CA-telomerase dual-hybrid inhibitors.

102 Here, we report an unexpected function of telomerase during cellular senescence and tumorigenesis.

103 Cancer cells rely on the enzyme telomerase (EC 2.7.7.49) to promote cellular immortality

104 lly validated structural model for how human telomerase engages TPP1 at telomeres, setting the stage

105 Telomerase enzymatic activity was not directly affected

106 We show that swapping in the telomerase essential N-terminal (TEN) and insertions in

107 AP) with unanticipated interactions with the telomerase essential N-terminal (TEN) domain and roles i

108 erase inhibition and DNA damage induction in telomerase-expressing cancer cells and paves the way for

109 s in syngeneic and humanized mouse models of telomerase-expressing cancers.

110 We quantified telomerase expression and telomere length (TL) in differ

111 the TERT promoter were associated with high telomerase expression evidently activating this tumor-dr

112 Telomerase expression is restricted in humans to certain

113 In addition to preventing senescence, telomerase expression maintained metabolic flux from glu

114 Lessening oxidative damage to DNA and telomerase expression through diet may represent an intr

115 ory cell infiltration in the kidney, reduces telomerase expression, and accelerates vascular senescen

116 Telomerase extends telomere sequences at chromosomal end

117 We conduct a series of direct telomerase extension assays in the presence of modified

118 nt advances have emerged in the telomere and telomerase fields.

119 olium TERT that has been used as a model for telomerase for over a decade.

120 s the species specificity of human and mouse telomerase for their cognate TPP1 partners.

121 Telomerase-free cancer cells employ a recombination-base

122 s in telomerase-relevant genes that decrease telomerase function cause a range of genetic disorders,

123 Genetic mutations that affect telomerase function or telomere maintenance result in a

124 taCEH and 1- and 2-bp alleles do not support telomerase function.

125 CHC8 associated with TR and was required for telomerase function.

126 folding synergizes with POT1-TPP1 to support telomerase function.

127 studies have revealed profound insights into telomerase functions, the low cellular abundance of func

128 The human telomerase gene (hTERT) is repressed in most somatic cel

129 intergenic region, introns 2 and 6 of human telomerase gene (hTERT) were critical for regulating its

130 lomeres even in the presence of a functional telomerase gene and that a new subtelomere was formed by

131 led a novel approach to engineer a humanized telomerase gene in mice, achieving a milestone in creati

132 and-in liver cancer-frequently activate the telomerase gene TERT.

133 wild-type and telomerase-deficient mice with telomerase gene therapy prevented the onset of lung prof

134 diverse fields associated with telomeres and telomerase have substantially matured.

135 method for the detection of protein kinases, telomerase, histone H3 methyltransferase SET7/9, and pol

136 or formation and nuclear localization of the telomerase holoenzyme.

137 ion products, we demonstrate here that human telomerase holoenzymes contain fast- and slow-acting cat

138 They endow native telomerase holoenzymes with the ability to match their t

139 gonucleotides that target the RNA subunit of telomerase, hTR, simultaneously inhibiting enzymatic act

140 studies (1.3 and 3.4 muM), was evaluated in telomerase immortalized gingival keratinocytes (TIGKs) b

141 o that a 3-hour MMC treatment of primary and telomerase immortalized human corneal limbal epithelial

142 n of host signaling proteins in decidualized telomerase-immortalized human endometrial stromal cells

143 was independent of immortalization, as human telomerase-immortalized normal oral keratinocytes suppor

144 y of most of the key molecular components of telomerase, implications for limits to cellular replicat

145 in the liver and testis, and upregulation of telomerase in brain and liver.

146 uld reverse these observations, we expressed telomerase in HMECs.

147 Thus, telomerase in mESCs with the hmTert alleles was subjecte

148 odels and intrinsic difficulties in studying telomerase in physiologically relevant cells, the molecu

149 Modalities to restore telomerase in stem cells throughout the body remain uncl

150 relocalization to nuclear pores early after telomerase inactivation.

151 ae, the complex life cycle and maturation of telomerase includes a cytoplasmic stage.

152 Here we discuss recent efforts targeting telomerase, including immunotherapies and direct telomer

153 hough there are some cancer cells that use a telomerase-independent mechanism of telomere extension,

154 ernative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism th

155 ny tumors maintain chromosome-ends through a telomerase-independent, DNA-templated mechanism called a

156 that specifically target hTR through potent telomerase inhibition and DNA damage induction in telome

157 Long-term telomerase inhibition in malignant cells results in prog

158 isms, such as DNA damage, DNA intercalation, telomerase inhibition, and apoptosis induction, have bee

159 esence of extra repeats have implications in telomerase inhibition, T-loop formation and telomere end

160 jugation and (111)In-labeling did not change telomerase inhibition.

161 Telomerase inhibitors (i.e., azidothymidine) can represe

162 However, development of telomerase inhibitors has been challenging and thus far

163 merase, including immunotherapies and direct telomerase inhibitors, as well as emerging approaches su

164 Additionally, we identified a telomerase inhibitory role when several native POT1-TPP1

165 mino acid L104 outside the TEL patch, TPP1's telomerase interaction domain, to telomere length contro

166 The telomerase interaction surface on human TPP1 has been ma

167 Part of the reactivation of telomerase involves the splicing of hTERT transcripts to

168 Telomerase is a ribonucleoprotein complex that counterac

169 Telomerase is a ribonucleoprotein complex, the catalytic

170 Telomerase is a specialized reverse transcriptase that a

171 his POT1-TPP1 complex-mediated inhibition of telomerase is abrogated in the context of the POT1 H266L

172 Telomerase is an attractive target for anti-tumor therap

173 Telomerase is an enzymatic ribonucleoprotein complex tha

174 Telomerase is expressed in adult mouse, but not in most

175 In some species, the enzyme telomerase is expressed in adult somatic tissues, and po

176 Telomerase is expressed in the majority (>85%) of tumors

177 Using this platform, we observed that while telomerase is highly expressed in hESCs, it is quickly s

178 Telomerase is pathologically reactivated in most human c

179 ides an experimental model to understand how telomerase is regulated in normal adult tissues.

180 expression of TERT, the catalytic subunit of telomerase, is a biological marker of progression in sev

181 oblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide aden

182 TPP1(L104A/L104A) cells respond to increased telomerase levels and maintain protected telomeres.

183 tricted in humans to certain cell types, and telomerase levels are tightly controlled in normal condi

184 telomeric retrotransposons that, instead of telomerase, maintain chromosome length in Drosophila.

185 Human telomerase maintains genome stability by adding telomeri

186 RNA tagging and challenge current models of telomerase maturation.

187 net G-strand growth is apparent, indicating telomerase-mediated G-strand extension.

188 oxidized dNTPs and therapeutic dNTPs inhibit telomerase-mediated telomere elongation.

189 that protects chromosome ends and regulates telomerase-mediated telomere extension.

190 reverse transcriptase or treatment with the telomerase-mediated telomere targeting agent 6-thio-2'de

191 mere shortening, the concept that inhibiting telomerase might be a successful therapeutic strategy an

192 on and secretion, is severely compromised in telomerase mutant cells with short telomeres.

193 In young telomerase mutants, proliferative tissues exhibit DNA da

194 ncing of p53 rescued hepatocyte formation in telomerase mutants.

195 ld be of interest not only for patients with telomerase mutations but also for sporadic cases of IPF

196 Strikingly, telomerase negative cells bypass senescence when express

197 ETV5 bound to the hTERT promoter in both telomerase-negative and -positive cells, but it activate

198 in significantly lower cytotoxic effects in telomerase-negative cell lines when compared with AZT tr

199 radiotoxicity and DNA damage was observed in telomerase-negative cells exposed to (111)In-Match oligo

200 er and altered histone modifications only in telomerase-negative cells.

201 tain their telomeres by either re-activating telomerase or adopting the homologous recombination (HR)

202 w 20% of cancer cells are maintained without telomerase or ALT.

203 oliferative capacity by either re-expressing telomerase or inducing alternative lengthening of telome

204 se core domain shared by DNA polymerases and telomerases, our results show the function of N- and C-t

205 so showed SnoopLigase-mediated coupling of a telomerase peptide relevant to cancer immunotherapy.

206 Kinetics reveal that telomerase poorly selects against 6-thio-dGTP, inserting

207 l radiolabeled oligonucleotide for targeting telomerase-positive cancer cells that exhibits dual acti

208 In telomerase-positive cancer cells, unlabeled Match oligon

209 of 5-MeCITP leads to telomere shortening in telomerase-positive cancer cells, while resulting in sig

210 oligonucleotide radiotherapeutics targeting telomerase-positive cancers.

211 n close proximity to nuclear Cajal bodies in telomerase-positive cells.

212 Addition of the telomerase processivity factor POT1-TPP1 altered the DNA

213 Furthermore, telomerase processivity factor POT1-TPP1 fails to restor

214 y assays, we discovered that TIN2 stimulated telomerase processivity in vitro All of the TIN2 isoform

215 t TIN2 functions with TPP1/POT1 to stimulate telomerase processivity.

216 tein levels, the abundance of Est1 and Est2 (telomerase proteins), and the processing of TLC1 (telome

217 Telomerase reactions performed with telomere DNA primers

218 In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or

219 Telomere maintenance via telomerase reactivation is a nearly universal hallmark o

220 Conversely, germline mutations in telomerase-relevant genes that decrease telomerase funct

221 Thus, telomerase represents an attractive target for highly se

222 omotes long interactions required for stable telomerase retention.

223 t cryoelectron microscopy map of Tetrahymena telomerase revealed the structure of a previously unchar

224 Telomerase reverse transcribes short guanine (G)-rich DN

225 HCC, the most frequently mutated genes were telomerase reverse transcriptase (TERT) (58.1%), catenin

226 Telomerase contains a catalytic core of telomerase reverse transcriptase (TERT) and telomerase R

227 Mutations in the genes encoding telomerase reverse transcriptase (TERT) and telomerase's

228 ex, the catalytic core of which includes the telomerase reverse transcriptase (TERT) and the non-codi

229 ure in MYCN nonamplified neuroblastomas with telomerase reverse transcriptase (TERT) gene overexpress

230 his study, we extend these observations into telomerase reverse transcriptase (TERT) immortalized ora

231 Because telomerase reverse transcriptase (TERT) is usually the l

232 Similarly, telomerase reverse transcriptase (tert) mutant zebrafish

233 determined structures of Tribolium castaneum telomerase reverse transcriptase (TERT) throughout its c

234 to mutations in the same genes, such as the telomerase reverse transcriptase (TERT), but through dif

235 riven by the transcriptional upregulation of telomerase reverse transcriptase (TERT).

236 ted RNA subunit and a reverse transcriptase (telomerase reverse transcriptase [TERT]).

237 oblasts transduced with genes encoding human telomerase reverse transcriptase and doxycycline-inducib

238 Mutations in the telomerase reverse transcriptase and telomerase RNA comp

239 nent and the N-terminally biotinylated human telomerase reverse transcriptase and using a newly devel

240 it is quickly silenced, specifically due to telomerase reverse transcriptase component (TERT) down-r

241 e hotspot integrations, such as those in the telomerase reverse transcriptase gene (TERT) promoter, a

242 Here, we uncovered that telomerase reverse transcriptase null (Tert(-/-)) mESCs

243 CRISPR/Cas9 knockout of human telomerase reverse transcriptase or treatment with the t

244 of 5-MeCITP bound to the Tribolium castaneum telomerase reverse transcriptase reveals an atypical int

245 Using Chlamydomonas and human telomerase reverse transcriptase-retinal pigment epithel

246 and T-motif in the RNA-binding domain of the telomerase reverse transcriptase.

247 The templating RNA is the core of the telomerase reverse transcriptase.

248 Furthermore, an evident up-regulation of telomerase reverse-transcriptase (TERT) expression was d

249 The telomerase ribonucleoprotein (RNP) counters the chromoso

250 (PARN) cause accumulation of extended human telomerase RNA (hTR) species and precipitate dyskeratosi

251 e stability of non-coding RNAs such as human telomerase RNA (hTR), but these effects do not explain t

252 ranscriptase (TERT) and the non-coding human telomerase RNA (hTR), which serves as a template for the

253 MS2 RNA tagging to image single molecules of telomerase RNA (hTR).

254 telomerase reverse transcriptase (TERT) and telomerase RNA (TER).

255 d in mutation carriers, genomically extended telomerase RNA (TR) accumulated at the expense of mature

256 The sensitive imaging of telomerase RNA (TR) in living cells is crucial for impro

257 e-molecule imaging unveils the life cycle of telomerase RNA and provides a framework to reveal how ca

258 Telomerase RNA and related noncoding RNAs require 3' end

259 Thus, the CEH is essential in yeast telomerase RNA because it is needed to bind TERT to form

260 on of telomere-length maintenance molecules [telomerase RNA component ( Terc; P < 0.01), P23 ( P = 0.

261 ound to regulate the maturation of the human telomerase RNA component (hTR), a noncoding RNA required

262 merase that oligoadenylates and destabilizes telomerase RNA component (TERC).

263 able cell line overexpressing both the human telomerase RNA component and the N-terminally biotinylat

264 in the telomerase reverse transcriptase and telomerase RNA component genes have been observed at a h

265 receptor tyrosine kinase, downregulates the telomerase RNA component TERC, confers genomic stability

266 omoter interactions (7SK), telomere biology (telomerase RNA component) and inflammatory gene regulati

267 Reduced levels of TERC, the telomerase RNA component, cause dyskeratosis congenita (

268 in previously unassigned density as well as telomerase RNA domains essential for activity.

269 we have mapped an essential binding site in telomerase RNA for TERT that is crucial to form the cata

270 stem were used to deliver APEX2 to the human telomerase RNA hTR with high specificity.

271 ) complex associates with and stabilizes the telomerase RNA in the cytoplasm and promotes its nuclear

272 sociated proteins TCAB1 and dyskerin and the telomerase RNA maturation component poly(A)-specific rib

273 ytoplasmic passage, the nuclear stability of telomerase RNA no longer depends on Mex67.

274 erase proteins), and the processing of TLC1 (telomerase RNA).

275 157-nucleotide (nt) Saccharomyces cerevisiae telomerase RNA, TLC1, is rapidly evolving, the central c

276 hat regulates the production of mature human telomerase RNA.

277 ately after transcription, newly synthesized telomerase RNAs undergo one round of nucleo-cytoplasmic

278 localize specifically in Cajal bodies, where telomerase RNP complex assembly takes place.

279 The telomerase RNP core enzyme is composed of a dedicated RN

280 telomerase reverse transcriptase (TERT) and telomerase's RNA components as well as shortened telomer

281 diated recruitment results in short telomere-telomerase scanning interactions, and then base pairing

282 Unfortunately, how telomerase selects correct nucleotides is unknown.

283 latively, our work provides insight into how telomerase selects the proper nucleotide to maintain tel

284 To map the telomerase side of the interface, we exploited the predi

285 and find that TEN and TRAP have coevolved as telomerase-specific domains.

286 the canonical active site to interact with a telomerase-specific hydrophobic pocket formed by motifs

287 ng TPP1 but dispensable for other aspects of telomerase structure or function.

288 tors NOVA1 and PTBP1 in cancer by regulating telomerase that is expressed in the vast majority of can

289 utions of telomere products, we globally fit telomerase time-series data to a kinetic model that conv

290 4 bp of core-enclosing helix is required for telomerase to be active in vitro and to maintain yeast t

291 in vitro All of the TIN2 isoforms stimulated telomerase to similar extents.

292 eric protein TPP1, reduce the recruitment of telomerase to the telomere.

293 The presence of any telomerase variant was associated with an increased numb

294 natural ends of linear chromosomes and that telomerase was a specific telomere-terminal transferase

295 ic analysis and the structure of Tetrahymena telomerase, we built a pseudoatomic model of human telom

296 ing RNA-dependent DNA polymerases, including telomerase, which have a dramatically augmented Thumb do

297 Saccharomyces cerevisiae telomerase, which maintains telomere length, is comprise

298 s to be done, effective strategies targeting telomerase will have a transformative impact for cancer

299 In vitro data show that 5-MeCITP inhibits telomerase with a similar potency as the clinically admi

300 ese findings reveal mechanisms for targeting telomerase with modified dNTPs in cancer therapy.