ライフサイエンスコーパス: uORF

1 uORF number, intercistronic distance, overlap with the C

2 uORF use depends on the Kozak sequence context of its st

3 uORFs can modulate translation or RNA stability and medi

4 uORFs may repress translation of their downstream main O

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

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

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

8 anslational inhibition mediated by the Her-2 uORF.

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

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

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

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

13 Our results support a model in which a uORF coding sequence impacts its regulatory functions by

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

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

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

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

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

19 We investigated the impact of an uORF coding region on gene regulation by assaying the fu

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

21 zak sequence context of its start codon, and uORFs with strong contexts promote nonsense-mediated mRN

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

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

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

25 tages of infection where membrane-associated uORF protein facilitates virus release.

26 he distinct piRNA biogenesis requirements at uORFs and UDRs.

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

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

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

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

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

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

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

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

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

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

37 our results reveal the global regulation by uORFs and microRNAs.

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

39 lear repression of downstream translation by uORFs/oORFs.

40 1 and attenuate leaky scanning that bypasses uORFs.

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

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

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

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

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

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

47 Unique dipeptide-coding uORFs and nucleotide motifs, such as '5'-UGA(C/G)GG-3',

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

49 An additional conserved uORF, herein referred to as ORF-Z, was also found in exo

50 ed the functions of evolutionarily conserved uORF-encoded peptides.

51 , we highlight several examples of conserved uORF nascent peptides that stall ribosomes to regulate g

52 Furthermore, variants creating uORFs that overlap the coding sequence show signals of s

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

54 Improving the D13N uORF initiation context also promoted NMD.

55 translation protects mRNA from degradation, uORF translation triggers mRNA decay in a UPF1-dependent

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

57 e shown that variants that create or disrupt uORFs can cause disease.

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

59 firmed by internal mutation analyses in each uORF.

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

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

62 d variants disrupting stop sites of existing uORFs, are under strong negative selection.

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

64 phenomenon that has never been described for uORFs.

65 ce preceding an upstream open reading frame (uORF) and downstream GFP drives a broad range of transla

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

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

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

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

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

71 nstrate that an upstream open reading frame (uORF) present in the 5' untranslated region of the Arabi

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

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

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

75 also harbour an upstream open reading frame (uORF) that is subject to strong purifying selection.

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

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

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 ation of upstream small open reading frames (uORF).

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

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

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

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

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

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

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

90 Upstream open reading frames (uORFs) are known to control the translation of mRNAs.

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 potent regulatory elements located in 5' mRNA

94 Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein tra

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

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

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

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

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

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

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

106 AUG-initiated upstream open reading frames (uORFs) that are a major contributor to translation repre

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

108 ncluding 1,329 upstream open reading frames (uORFs) within the 5' untranslated regions of annotated c

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

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

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

112 with multiple upstream Open Reading Frames (uORFs), thereby activating stress-responsive gene expres

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 NAs harbouring upstream open reading frames (uORFs).

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

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

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

120 Our results highlight uORF-perturbing variants as an under-recognised function

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

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

123 that both codon identity and position impact uORF function.

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

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

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

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

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

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

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

131 Our findings provide insights into uORF-mediated translational regulation that can regulate

132 s that regulation of PHO1 expression via its uORF might be a genetic resource useful-both in natural

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

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

135 ctional peptides, the coding regions of most uORFs are not conserved.

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

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

138 ortant disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromat

139 63 nucleotides), or three (-213 nucleotides) uORFs.

140 , human cytomegalovirus, we uncover numerous uORFs and iORFs conserved across betaherpesviruses and w

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

142 poliovirus 1, we confirmed the expression of uORF protein in infected cells.

143 Thus, the importance of uORF coding sequences on their regulatory functions rema

144 mouse fibroblasts, suggesting involvement of uORF usage and reinitiation in clock regulation.

145 5'-leader add complexity into the nature of uORF-mediated translation control mechanisms during eIF2

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

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

148 egulatory functions by altering the speed of uORF translation.

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

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

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

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

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

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

155 While a minority of uORFs encode conserved functional peptides, the coding r

156 dentify specific genes where modification of uORFs likely represents an important disease mechanism,

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

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

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

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

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

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

163 The translation of uORFs can also affect mRNA stability.

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

165 Translation of uORFs usually inhibit the translation of downstream main

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

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

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

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

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

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

172 osomes translate the 5'-proximal short ORFs (uORFs) of piRNA precursors.

173 ding frames (ORFs), including upstream ORFs (uORFs) and internal ORFs (iORFs), generating a complete

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

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

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

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

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

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

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

181 lation of specific mRNAs with upstream ORFs (uORFs) situated in their 5'-leader regions.

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

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

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

185 n differentiated human intestinal organoids, uORF protein-knockout echoviruses are attenuated compare

186 established a slightly 5'-extended original uORF.

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

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

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

190 ified the inhibitory effect of the rice PHO1 uORF on translation in protoplasts.

191 A point mutation removing the PHO1 uORF (DeltauORF) in transgenic Arabidopsis resulted in i

192 how that natural accessions lacking the PHO1 uORF exhibit higher PHO1 protein levels and shoot Pi con

193 ontent was linked to the absence of the PHO1 uORF in a population of F2 segregants.

194 We identified the PHO1 uORF in genomes of crops such as rice (Oryza sativa), ma

195 th increased ribosome occupancy and possible uORF activation upon eIF4A2 binding.

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

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

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

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

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

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

202 to regulation over constitutively repressive uORFs/oORFs.

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

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

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

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

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

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

209 nserved across betaherpesviruses and we show uORFs are enriched in late viral genes.

210 g data to identify statistically significant uORFs.

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

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

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

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

215 Clock 5' UTR mutants, we mapped the specific uORF through which DENR acts to regulate CLOCK protein b

216 Inhibitory functions of such uORFs were abrogated by overexpression of complementary

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

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

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

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

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

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

223 The uORF-mediated polyamine responsive autoregulatory circui

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

239 ates the translocation of ribosomes into the uORF downstream regions (UDRs).

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

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

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

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

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

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

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

247 es), we also demonstrated translation of the uORF in representative members of the predominant human

248 Interestingly, deletion of the uORF led to higher shoot Pi content and was associated w

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

250 The presence of the uORF strongly inhibited the translation of a PHO1 5'UTR-

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

272 ve to override the inhibitory effects of the uORFs.

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

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

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 Some of these uORF-encoded nascent peptides enable responses to specif

278 These uORFs are unfavorable for re-initiation after terminatio

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

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

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

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

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

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 Contrary to uORFs, we find that translation of dORFs enhances transl

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

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

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

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

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

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

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

294 Varying uORF codons resulted in a wide range of functions, inclu

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

296 red elongation and translational control via uORFs.

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

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

299 codons resulted in the most inhibitory YAP1 uORF variants.

300 s of thousands of variants in the yeast YAP1 uORF.