ライフサイエンスコーパス: uORF

1 uORF number, intercistronic distance, overlap with the C

2 uORFs can modulate translation or RNA stability and medi

3 d that inhibition of translation by the -105 uORF occurred only in the cis configuration and not in t

4 d that inhibition of translation by the -105 uORF was independent of the encoded peptide sequence.

5 The Neurospora crassa arg-2 uORF encodes the 24-residue arginine attenuator peptide

6 anslational inhibition mediated by the Her-2 uORF.

7 ific translational repressor, GLD-1; and (2) uORF elicited regulation, mainly through NMD.

8 Finally, we report that 5 uORF-altering mutations, detected within genes previousl

9 ranslational control of genes harboring a 5' uORF can be modulated by elements in their 3' UTRs.

10 ee in-frame stop codons to nonstop codons, a uORF-ORF1 fusion protein was made, and virus replicated

11 on along with a U112A mutation to maintain a uORF-harboring stem-loop 4 structure, an unimpaired viru

12 f uAUG recognition modulates the impact of a uORF but steps during and after translation of the uORF

13 Translation of a uORF can produce a cis-acting peptide that causes effect

14 th the altered uORFs' sequences that abolish uORF regulation in vivo.

15 The ACC1 uORF is relevant for cell division because its ablation

16 ylation and translation of the 48-amino acid uORF.

17 orter gene placed downstream of the AdoMetDC uORF directly correlated with the stability of the ribos

18 applied a novel machine learning algorithm (uORF-seqr) to ribosome profiling data to identify statis

19 ditionally identify polymorphisms that alter uORF presence in 509 human genes.

20 ause was greatly diminished with the altered uORFs' sequences that abolish uORF regulation in vivo.

21 red by passage 10, which generated alternate uORFs that correlated with restored WT growth kinetics.

22 Although uORFs are present in approximately half of human and mou

23 ely truncated, reinitiation downstream of an uORF of 105nt is found to be just detectable, and increa

24 ion occurs independent of eIF2alpha-P via an uORF that allows for translation reinitiation at the CRe

25 TR and 3' UTR contain conserved elements and uORFs that may function in cytoplasmic regulation of gen

26 e reporter showed that the 5'UTR without any uORF (-98 nucleotide) expressed maximal luciferase activ

27 The Arabidopsis uORF and its maize (Zea mays) homolog repressed the tran

28 ble, and increases markedly in efficiency as uORF length is reduced to 15nt.

29 ding purified eIF2 increased reinitiation at uORFs 3 or 4 and reduced reinitiation at Gcn4p.

30 Although intriguing, these non-AUG uORF predictions have been made without statistical cont

31 We found that AUG and non-AUG uORFs are both frequently found in Saccharomyces yeasts.

32 Although most non-AUG uORFs are found in only one species, hundreds have eithe

33 However, non-AUG uORFs are translated less efficiently than AUG-uORFs and

34 ese results suggest that a subset of non-AUG uORFs may play important roles in regulating gene expres

35 e genomics approach to study AUG and non-AUG uORFs.

36 ween species at rates similar to that of AUG uORFs.

37 cient ORF translation; by contrast, some AUG uORFs, often exposed by regulated 5' leader extensions,

38 RFs are translated less efficiently than AUG-uORFs and are less subject to removal via alternative tr

39 lling reveals that sequence features at both uORFs and CDSes modulate the translation of CDSes.

40 mes initiate translation efficiently at both uORFs and ribosomes that had translated uORF1 efficientl

41 , and Neurospora crassa arg-2, regulation by uORFs controls expression in response to specific physio

42 lear repression of downstream translation by uORFs/oORFs.

43 1 and attenuate leaky scanning that bypasses uORFs.

44 xperimental studies have suggested candidate uORF regulation across the genome.

45 , NMD-sensitive transcript isoforms carrying uORFs or starting downstream of the ATG START codon.

46 o define the inhibitory features of the CHOP uORF and the biological consequences of loss of the CHOP

47 biological consequences of loss of the CHOP uORF on CHOP expression during stress.

48 ered that specific sequences within the CHOP uORF serve to stall elongating ribosomes and prevent rib

49 As a consequence, deletion of the CHOP uORF substantially increases the levels and modifies the

50 Ribosome occupancy at near-cognate uORFs was associated with more efficient ORF translation

51 The GCN4 and CPA1 uORFs thus control translation in fundamentally differen

52 nd induced NMD of CPA1-LUC; the mutated D13N uORF, which eliminates stalling and regulation, did not.

53 Improving the D13N uORF initiation context also promoted NMD.

54 nalysis of RNA degradome data, we discovered uORFs and CDS regions potentially associated with stacke

55 nd demonstrate that mutation of the dominant uORF restricts KSHV replication.

56 firmed by internal mutation analyses in each uORF.

57 am is characterized by persistently elevated uORF mRNA translation and concurrent gene expression rep

58 We report expression control by engineering uORFs and translation initiation to be robust, predictab

59 olution has targeted these features to favor uORFs amenable to regulation over constitutively repress

60 phenomenon that has never been described for uORFs.

61 An upstream open reading frame (uORF) confers the translational control of ACC1 and adju

62 n AUG-initiated upstream open reading frame (uORF) encoding a potential polypeptide of 3 to 13 amino

63 RNA contains an upstream open reading frame (uORF) encoding the arginine attenuator peptide (AAP).

64 d by a 38-codon upstream open reading frame (uORF) in the 5' leader.

65 ream of a short upstream open reading frame (uORF) in the 5' untranslated region of a gene, posttermi

66 cis-regulatory upstream open reading frame (uORF) in the 5' untranslated regions (5' UTRs) of both m

67 dependent on an upstream open reading frame (uORF) in the INO2 leader.

68 e product of an upstream open reading frame (uORF) in the mRNA is solely responsible for polyamine re

69 regulated by an upstream open reading frame (uORF) located in its 5' untranslated region.

70 a 48-amino acid upstream open reading frame (uORF) present within the 5'-leader of the transporter mR

71 ence of a short upstream open reading frame (uORF) resulting in the mitochondrial isoform being about

72 RNA contains an upstream open reading frame (uORF) that is absent in all shorter transcripts.

73 ly described an upstream open reading frame (uORF) that is responsible for repression of translation

74 es a cis-acting upstream open reading frame (uORF) that represses the translation of the downstream G

75 ntly translated upstream open reading frame (uORF) that represses translation of the main coding ORF

76 tion of a small upstream open reading frame (uORF) within the IRES and phosphorylation of the transla

77 ained within an upstream open reading frame (uORF), and its activity seems to be masked by translatio

78 by a regulatory upstream open reading frame (uORF).

79 n out-of-frame, upstream open reading frame (uORF).

80 codons or short upstream open reading frame (uORFs).

81 by inhibitory upstream Open Reading Frames (uORF) in their 5' UTRs.

82 2 mRNA has two upstream open reading frames (uORF), resulting in two premature stop codons.

83 ation of upstream small open reading frames (uORF).

84 AUG)-initiated upstream open reading frames (uORFs) (nAuORFs 1 and 2) occur in GCN4 mRNA upstream of

85 x landscape of upstream open reading frames (uORFs) across 5'-untranslated regions (UTRs) of key sign

86 nd function of upstream open reading frames (uORFs) across vertebrates.

87 there are two upstream open reading frames (uORFs) acting in a fail-safe manner to inhibit the trans

88 Upstream open reading frames (uORFs) are elements found in the 5'-region of an mRNA tr

89 ely translated upstream open reading frames (uORFs) are enriched in transcription factor mRNAs and pr

90 Upstream open reading frames (uORFs) are frequently present in the 5'-leader regions o

91 Upstream open reading frames (uORFs) are known to regulate a few specific transcripts,

92 s harboring 5' upstream open reading frames (uORFs) are often found in genes controlling cell growth

93 Upstream open reading frames (uORFs) are ubiquitous repressive genetic elements in ver

94 ntaining three upstream open reading frames (uORFs) from the 5'-UTR dramatically increased GUS expres

95 e regulated by upstream open reading frames (uORFs) in a manner of re-initiation.

96 d by the three upstream open reading frames (uORFs) in its 5' untranslated region.

97 ains potential upstream open reading frames (uORFs) in the 5' untranslated region (UTR) starting at -

98 he presence of upstream open reading frames (uORFs) in the 5'-untranslated region (5'-UTR) of TMEFF2.

99 r exclusion of upstream open reading frames (uORFs) in the 5'UTR as well as Alu-elements and microRNA

100 heir 3'UTR and upstream open reading frames (uORFs) in their 5 UTR than do control mRNAs.

101 which multiple upstream open reading frames (uORFs) interact to regulate translation in higher eukary

102 ranscript with multiple open-reading frames (uORFs) is considered as a regulatory unit for translatio

103 nvolving short upstream open reading frames (uORFs) located in the 5' untranslated region.

104 l involves two upstream open reading frames (uORFs) located in the 5'-leader of the ATF5 mRNA, a feat

105 served peptide upstream open reading frames (uORFs) of Arabidopsis and rice, we found a predominance

106 This includes upstream open reading frames (uORFs) present in mRNAs controlled by the integrated str

107 stream AUGs (uAUGs) and open reading frames (uORFs) profoundly affect the translation of the primary

108 A sequences in upstream open reading frames (uORFs) to specifically increase the amounts of protein t

109 ons with short upstream open reading frames (uORFs) within the 5'untranslated region.

110 e composition, upstream open reading frames (uORFs), and secondary structure.

111 (NMD) targets, upstream open reading frames (uORFs), canonical ORFs shorter than approximately 590 nt

112 Upstream open reading frames (uORFs), located in transcript leaders (5' UTRs), are pot

113 often contain upstream open reading frames (uORFs).

114 codons and six upstream open reading frames (uORFs).

115 controlled by upstream open reading frames (uORFs).

116 t contains two upstream open-reading frames (uORFs).

117 ing to several upstream open reading frames (uORFs).

118 nd up to three upstream open reading frames (uORFs).

119 r more short 'upstream' open reading frames, uORFs, precede the initiator of the main coding sequence

120 identified signature translation events from uORFs in the 5' untranslated region of binding immunoglo

121 Importantly, alterations in the GADD34 uORF affect the status of eIF2alpha-P, translational con

122 ution ribosome footprinting, we find that (i)uORFs are prevalent within vertebrate transcriptomes, (i

123 w signatures of active translation, and (iii)uORFs act as potent regulators of translation and RNA le

124 e results suggest that the regulated step in uORF translation is after formation of the peptidyl-tRNA

125 eased global protein synthesis and increased uORF mRNA translation are followed by normalization of p

126 after translation of the uORF also influence uORF function.

127 ence of stress, translation of an inhibitory uORF in GADD34 acts as a barrier that prevents reinitiat

128 gs reveal that translation of two inhibitory uORFs encoded by noncanonical CUG and UUG initiation cod

129 The AUG-initiated uORF is presumably translated following genomic 5'-end c

130 GCN4 mRNA upstream of the four AUG-initiated uORFs (uORFs 1-4) that regulate GCN4 translation.

131 nitiation factor eIF2A and non-AUG-initiated uORFs.

132 Potential CUG-initiated uORFs are also found in many strains.

133 hanism of translation reinitiation involving uORFs is conserved from yeast to mammals.

134 CA-ROP2 is efficient in loading uORF-containing mRNAs onto polysomes and stimulates tran

135 tumor suppressor genes which also bear long, uORF-containing, 5'-UTRs, or through interactions with R

136 The roles of many uORFs that are identified by genome-level approaches, as

137 The 5'-most uORF (uORF1) alone suppresses downstream translational a

138 By also using multiple uORFs in series and non-AUG start codons, we were able t

139 her, our data indicate that the noncanonical uORF is translated and encodes a peptide that functions

140 63 nucleotides), or three (-213 nucleotides) uORFs.

141 s, as are 74% of pseudogene peptides, 24% of uORF peptides and 32% of dORF peptides.

142 the mechanisms underlying the known cases of uORF-mediated control but also to define the full comple

143 ol but also to define the full complement of uORF-containing mRNAs in at least one fungal organism.

144 5'-leader add complexity into the nature of uORF-mediated translation control mechanisms during eIF2

145 ndividual genes by their uORFs, the range of uORF-mediated translational repression in vertebrate gen

146 of TOR, and thus translation reinitiation of uORF-containing mRNAs.

147 ibosomes at the M27 AUG after termination of uORF translation or new initiation by ribosomes skipping

148 rable for re-initiation after termination of uORF translation.

149 is unclear whether the repressive effects of uORFs are conserved across species.

150 This review presents key features of uORFs that serve to optimize translational control that

151 range of mutations and the identification of uORFs suggest further complexity in the regulation of LM

152 hh pathway, we demonstrate the importance of uORFs within the major SHH receptor, Ptch1, in control o

153 ader region results in a different number of uORFs and variability in the size of uORF2.

154 and mouse, and correlates with the number of uORFs.

155 Recognizing the potential of uORFs in regulating translation expands our understandin

156 we observe that the regulatory potential of uORFs on individual genes is conserved across species.

157 directly measure the translation products of uORFs during the ISR.

158 These results show that properties of uORFs that permit ribosome reinitiation are critical for

159 profiling studies suggest that thousands of uORFs initiate with non-AUG start codons.

160 The translation of uORFs can also affect mRNA stability.

161 They focus the translation of uORFs on uORF1 and attenuate leaky scanning that bypasse

162 and its regulated activity was dependent on uORF translation.

163 d 125 containing two start codons within one uORF that is required and sufficient for repression of p

164 a, C/EBPdelta and ATF4 that have G/C rich or uORF sequences in their 5' UTR.

165 a mechanism involving a single upstream ORF (uORF) located in the 5'-leader of the CHOP mRNA.

166 bosome bypass of an inhibitory upstream ORF (uORF) situated in the 5'-leader of the CHOP mRNA.

167 ated region (UTR) generates an upstream ORF (uORF) that affects both the background expression of thi

168 ted mRNAs, 30% had one or more upstream ORF (uORF) that influenced the number of ribosomes on the pri

169 Upstream ORFs (uORFs) are mRNA elements defined by a start codon in the

170 regulatory features by which upstream ORFs (uORFs) direct downstream translation control and express

171 TOR) promotes reinitiation at upstream ORFs (uORFs) in genes that play important roles in stem cell r

172 ferential contribution of two upstream ORFs (uORFs) in the 5' leader of the mouse ATF4 mRNA.

173 Short, upstream ORFs (uORFs) located in the 5'-leader of the mRNA can be selec

174 on factor ATF4 through paired upstream ORFs (uORFs) plays an important role in eukaryotic gene regula

175 of BACE1 mRNA contains three upstream ORFs (uORFs) preceding the BACE1 initiation codon.

176 Insertion of these upstream ORFs (uORFs) resulted in suppression of protein expression.

177 mRNA, with its two conserved upstream ORFs (uORFs), in this translational regulation.

178 changes the inclusion of long upstream ORFs (uORFs).

179 f many genes is controlled by upstream ORFs (uORFs).

180 f GADD34 and CReP contain two upstream ORFs (uORFs).

181 established a slightly 5'-extended original uORF.

182 Finally, 5MP and the paired uORFs allowing ATF4 control are conserved in the entire

183 ave identified 44 putative conserved peptide uORFs (CPuORFs) in Drosophila melanogaster that show evi

184 We propose that persistent uORF translation, for a variety of chaperones, shelters

185 CN4 mediated by short upstream open reading (uORFs) in response to eIF2 phosphorylation.

186 stream of the primary protein-coding region (uORFs) and 4% are translated downstream (dORFs).

187 ression of the ribosome through a regulatory uORF, which depends on the physiological state of the ce

188 This regulatory uORF-encoded peptide, which is evolutionarily conserved

189 Furthermore, they show that regulatory uORFs are conserved across species and subject to select

190 alysis suggests that at least two regulatory uORFs (namely, in SLC35A4 and MIEF1) encode functional p

191 to regulation over constitutively repressive uORFs/oORFs.

192 tion of TMEFF2 via a mechanism that requires uORFs in the 5'-UTR of TMEFF2.

193 ed sequence or position within Saccharomyces uORFs initiating with UUG are particularly common and ar

194 In PC12 cells, however, the second uORF appears to be translated.

195 sing reporter constructs to test 25 selected uORFs, we estimate that uORFs typically reduce protein e

196 results and the analysis of a frame-shifted uORF, in which the repression capability was lost, indic

197 region (UTR) of Her-2 mRNA contains a short uORF that represses translation of the downstream coding

198 nts with uncoupled chloroplasts did not show uORF-dependent repression.

199 istent with a model in which ribosomes shunt uORF-containing segments of the 5' leader as the ribosom

200 g data to identify statistically significant uORFs.

201 AIRAP transcript contains a single uORF in a poor-kozak context.

202 P1R15B and IFRD1) demonstrated that a single uORF is sufficient for eIF2-mediated translation control

203 by bypassing poor kozak context of a single uORF transcript.

204 Some uORFs may have regulatory roles, while others may exist

205 belongs to the class of "sequence-specific" uORFs.

206 to test 25 selected uORFs, we estimate that uORFs typically reduce protein expression by 30-80%, wit

207 We find that uORFs are depleted near coding sequences (CDSes) and hav

208 These results support the hypothesis that uORFs in mouse MOR mRNA act as negative regulators throu

209 Here, we report that uORFs correlate with significantly reduced protein expre

210 Together, our results suggest that uORFs influence the protein expression of thousands of m

211 The uORF is predicted to initiate at a noncanonical codon (A

212 The uORF-mediated polyamine responsive autoregulatory circui

213 t the 5'UTR of MRP2 mRNA transcripts and the uORF at -105 markedly influence MRP2 translation.

214 of AIRAP is solely dependent on eIF1 and the uORF kozak context.

215 rmination codon of uORF1 was mutated and the uORF was linked in-frame with the GFP ORF, enabling visu

216 ikely an ancient mechanism of control as the uORF is conserved in GGP genes from mosses to angiosperm

217 which regulation of ribosome pausing at the uORF by polyamines controls ribosome access to the downs

218 which do not induce ribosome stalling at the uORF of the ermC resistance gene, trigger its expression

219 nascent AAP causes ribosomes to stall at the uORF stop codon in response to arginine, thus, blocking

220 AAP's function of stalling ribosomes at the uORF termination codon.

221 arginine (Arg) by stalling ribosomes at the uORF termination codon.

222 Ketolides promote frameshifting at the uORF, allowing the translating ribosome to invade the in

223 h a lower translation initiation rate at the uORF, more ribosomes "leak" past the uORF; consequently,

224 h the stability of the ribosome pause at the uORF.

225 on of high levels of ribosomes with both the uORF and the main coding sequence of GGP.

226 nitiation at the M1 AUG is restricted by the uORF, while expression of the nuclear isoform requires r

227 In conclusion, the uORF found in the extended, overlapping 5'-UTR AS mRNA s

228 overned simply by ribosomes encountering the uORF terminator but appeared dependent on the AAP's ribo

229 e uORF in-frame, and mutations to extend the uORF, demonstrated functionality, both in vitro with AS

230 m and Interpro domain analyses, genes in the uORF dataset show a higher frequency of ORFs implicated

231 ut steps during and after translation of the uORF also influence uORF function.

232 te components, (i) active translation of the uORF and (ii) sequence-specific characteristics of the s

233 vary the translation initiation rate of the uORF and subsequently control the degree of this suppres

234 xpression, whereas specific silencing of the uORF AS mRNAs resulted in the coordinate up-regulation o

235 vity 2- to 3-fold, whereas disruption of the uORF at nucleotide -149 had little effect.

236 Disruption of the uORF by site-directed mutagenesis at nucleotide -109 enh

237 Translation of the uORF can also control gene expression by affecting the s

238 ng stress facilitates ribosome bypass of the uORF due to its poor start site context, and instead it

239 fore initiating ribosomes at the AUGs of the uORF fail to efficiently initiate translation at the sta

240 low eIF2 phosphorylation, translation of the uORF serves as a barrier that prevents translation of th

241 Overexpression of the uORF suppressed endothelial AS protein expression, where

242 ered by increased ribosomal occupancy of the uORF termination codon.

243 Expression of the full-length of the uORF was necessary to mediate a trans-suppressive effect

244 during stress directs ribosome bypass of the uORF, facilitating translation of the GADD34 coding regi

245 length or position, or other features of the uORF, rather than the peptide it encodes, that determine

246 stalling of the ribosomes at the end of the uORF.

247 at or close to the termination codon of the uORF.

248 at the uORF, more ribosomes "leak" past the uORF; consequently, more ribosomes are able to reach and

249 Single base insertions to place the uORF in-frame, and mutations to extend the uORF, demonst

250 By varying the base sequence preceding the uORF, we sought to vary the translation initiation rate

251 or new initiation by ribosomes skipping the uORF and the M1 AUG.

252 sion capability was lost, indicated that the uORF causes ribosome stalling.

253 Cca1 nucleotidyltransferase suggest that the uORF length-dependence of changes in reinitiation compet

254 These results together suggest that the uORF represses ORF1 translation yet plays a beneficial b

255 that among the uORFs in the Mrp2 5'UTR, the uORF starting at nucleotide -109 probably plays an impor

256 In vitro, the uORF-disrupting nondeletion mutants showed enhanced tran

257 (i) When the uORF AUG-initiating codon was replaced with a UAG stop c

258 (ii) When the uORF was fused with genomic (main) ORF1 by converting th

259 se transformed with a construct in which the uORF was mutated exhibited serrated leaves, compact rose

260 Mutagenesis of the two AUG codons within the uORF is sufficient to reduce translational repression.

261 iotics promote translation arrest within the uORF, and the static ribosome induces a conformational c

262 sequence of known RARbeta2, but lack all the uORFs present in the full-length 5'-UTR.

263 We conclude that among the uORFs in the Mrp2 5'UTR, the uORF starting at nucleotide

264 chanisms to explain how ribosomes bypass the uORFs, including reinitiation, leaky scanning, and inter

265 We demonstrate that disrupting the uORFs results in markedly increased translation efficien

266 Disruption of the uORFs at -105 and -74 nucleotides by mutation of ATGs to

267 nitiation mechanism after translation of the uORFs enables ORF36 expression.

268 Disruption of the uORFs had no effect on translation in B104 cells, which

269 ve to override the inhibitory effects of the uORFs.

270 NMD, likely by repressing translation of the uORFs.

271 Leaky scanning past the uORFs facilitates ORF35 expression, while a reinitiation

272 d on the nucleotide sequence surrounding the uORFs in the 5' leader, the order of the two uORFs in th

273 omes were differentially associated with the uORFs elements and coding region under different growth

274 econdary structure or rare codons within the uORFs.

275 the regulation of individual genes by their uORFs, the range of uORF-mediated translational repressi

276 These uORF-dependent changes suggest that alpha-1-antitrypsin

277 These uORFs are unfavorable for re-initiation after terminatio

278 ic approaches we show that features of these uORFs are central for their differential expression.

279 bserved facilitated ribosome bypass of these uORFs, allowing for increased translation of the EPRS co

280 This uORF encodes a highly conserved peptide (CPuORF) that is

281 expressing CPA1-LUC, we determined how this uORF contributes to NMD control.

282 Disruption of this uORF stops the ascorbate feedback regulation of translat

283 ty seems to be masked by translation of this uORF.

284 egion (UTR) of mouse MOR mRNA contains three uORFs preceding the MOR main initiation codon.

285 ration are preferentially translated through uORF-mediated mechanisms during activation of the integr

286 s and upstream regions of known transcripts (uORFs).

287 se ribosome profiling to identify translated uORFs and measure their effects on downstream translatio

288 through delayed re-initiation involving two uORFs in the mRNA leader.

289 The occurrence of two uORFs with differing activities in both the human gene a

290 The cooperation between the two uORFs and the three proteins formed a multiple fail-safe

291 The different activities of the two uORFs do not depend on the nucleotide sequence surroundi

292 uORFs in the 5' leader, the order of the two uORFs in the 5' leader, or the occurrence of secondary s

293 Elimination of these two uORFs raises the translational efficiency of the transcr

294 The wild-type uORF exerted translational control and induced NMD of CP

295 ustrate the roles that previously unexamined uORFs with noncanonical initiation codons can play in mo

296 NA upstream of the four AUG-initiated uORFs (uORFs 1-4) that regulate GCN4 translation.

297 ns suggest that the prevalence of vertebrate uORFs may be explained by their conserved role in repres

298 red elongation and translational control via uORFs.

299 Modeling supported a mechanism where uORFs shunt the flow of ribosomes away from the downstre

300 ion of ATF4 and potentially other genes with uORFs in their mRNA leaders through delayed re-initiatio