ライフサイエンスコーパス: R-loop

1 NA replication via aberrant RNA-DNA hybrids (R-loops).

2 nct structures and promotes RNA*DNA hybrids (R-loops).

3 quence is necessary and sufficient to induce R-loop.

4 displacing the non-target strand, forming an R-loop.

5 ing of the entire protospacer to form a full R-loop.

6 plication protein A (RPA)-coated centromeric R loops.

7 the nuclear pore helps restrain pathological R loops.

8 deaminase (AID) to identify genes preventing R loops.

9 1/2 mutants, indicating that Mlp1/2 prevents R loops.

10 on of current genomic strategies for mapping R loops.

11 ds and stimulates the activity of RNaseH1 on R loops.

12 by RNA-DNA hybrids, commonly referred to as R-loops.

13 rotein transcription complex and by removing R-loops.

14 s are significantly enriched at regions with R-loops.

15 trans by formation of lncRNA-DNA hybrids or R-loops.

16 e in the hostile condition by removing these R-loops.

17 is affected by mutations in genes regulating R-loops.

18 motes transcription termination by resolving R-loops.

19 all biochemically established properties of R-loops.

20 ed to form following removal of the RNA from R-loops.

21 strates for the formation of transcriptional R-loops.

22 oops induced greater instability than single-R-loops.

23 hat dsRNAs can interfere with its binding to R-loops.

24 vement in the mammalian nucleus by resolving R-loops.

25 zymes that help resolve replication-impeding R-loops.

26 s to suppress RNAP I transcription-associate R-loops.

27 O collisions leading to genome-destabilizing R-loops.

28 breakage and contractions in the presence of R-loops.

29 R loop, a transcription intermediate containing RNA:DNA

30 R-loop, a three-stranded RNA/DNA structure, has been lin

31 GC skew favors R-loops, a type of three stranded nucleic acid structure

32 R-loops accumulate in nucleoli during RNA polymerase I (

33 Here we show that R-loops accumulate preferentially in breast luminal epit

34 and Top1 along rDNA coincided at sites where R-loops accumulated in mammalian cells.

35 In the absence of Top1 or RNase Hs, R-loops accumulated to substantially higher extent when

36 chia coli or Saccharomyces cerevisiae caused R-loop accumulation along rDNA.

37 an important contributor to BRCA1-associated R-loop accumulation and breast cancer development.

38 using and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-k

39 We show that SGS1 loss increases R-loop accumulation and sensitizes cells to transcriptio

40 ether, our findings support a model in which R-loop accumulation and subsequent DNA damage sequesters

41 nd this gene deleted strain showed increased R-loop accumulation as compared to the wild type.

42 Here, we report that R-loop accumulation at a guanine-rich sequence, which is

43 lar mechanism by which the FA pathway limits R-loop accumulation requires FANCM translocase activity.

44 increased RNA synthesis, which together with R-loop accumulation results in replication fork slowing

45 Loss of either RNase H1 or Top1 caused R-loop accumulation, and the accumulation of R-loops was

46 increased DNA damage-induced cell death and R-loop accumulation.

47 isulfite-based approach, bisDRIP-seq, to map R-loops across the genome at near-nucleotide resolution

48 -density in permitting the elongation of the R-loop, after it had initiated.

49 Here, we show that persistent R-loops also compromise DNA repair.

50 reased replication fork speed, and increased R-loops), an apoptotic response, and a dependence upon c

51 e and replication stress, RPA is a sensor of R loops and a regulator of RNaseH1, extending the versat

52 in cells, and loses the ability to suppress R loops and associated genomic instability.

53 romosome segregation, revealing functions of R loops and ATR in suppressing chromosome instability.

54 G islands, together with the accumulation of R-loops and cytosolic ssDNA.

55 Significantly, increased cellular load of R-loops and DSBs, which are normalized on RNaseH1-mediat

56 Yeast lacking SGS1 accumulate R-loops and gamma-H2A at sites of Sgs1 binding, replicat

57 e that strong folding of nascent RNA weakens R-loops and hence decreases mutagenesis.

58 ese studies provide a high-resolution map of R-loops and identify gene structure as a critical determ

59 ient in two RNase H enzymes that remove both R-loops and incorporated ribonucleotides (rNs) from DNA,

60 IPc-seq method to sequence the RNA strand of R-loops and obtain strand-specific R-loop maps at near n

61 grity by concomitantly minimizing persistent R-loops and promoting repair of DNA double strand breaks

62 WASp deficiency provokes increased R-loops and R-loop-mediated DSBs in TH1 cells relative t

63 eomes and provide a mechanistic link between R-loops and RDDs.

64 Here we reveal an unanticipated link between R-loops and RNA-interference-dependent H3K9me2 formation

65 To determine the contribution of R-loops and rNMP in DNA to the defects observed in AGS,

66 However, the location of promoter-associated R-loops and the genomic domains they perturb to modify g

67 ed by cytosine deamination of DNA engaged in R-loops and the other by MutLgamma cleavage.

68 e report elevated levels of DNA-RNA hybrids (R-loops) and double strand breaks in rat neurons, human

69 R loops are three-stranded nucleic acid structures that

70 In intron-containing genes, R-loops are bounded between the transcription start site

71 Interestingly, we note that most mapped R-loops are each linked to a nearby free RNA end; by usi

72 R-loops are enriched at promoters where they have recent

73 Furthermore, R-loops are enriched at the 5' end of those genes with p

74 R-loops are features of chromatin consisting of a strand

75 R-loops are known to interfere with replication forks, a

76 Although R-loops are normal transcriptional intermediates, they a

77 ammalian class switch recombination regions, R-loops are obligatory intermediates.

78 se H1 associated with mitochondrial disease, R-loops are of low abundance, and there is mitochondrial

79 Furthermore, we have previously shown that R-loops are particularly enriched over G-rich terminator

80 R-loops are prevalent, collectively occupying up to 5% o

81 R-loops are three-stranded nucleic acid structures forme

82 The boundaries of R-loops are well-documented at immunoglobulin heavy chai

83 increasingly strong case has been built for R loops as potential regulators of gene expression.

84 A helicase Dbp2 regulates formation of these R-loops as genomic deletion or nuclear depletion results

85 mutants to translation inhibition points to R-loops as precursors for R-lesions.

86 At promoters, R-loops associate with a hyper-accessible state characte

87 By contrast, terminal R-loops associate with an enhancer- and insulator-like s

88 Detailed epigenomic profiling revealed that R-loops associate with specific chromatin signatures.

89 3 participate in the prevention or repair of R loop-associated DNA damage, a manifestation of aberran

90 confirms a role for Sgs1/BLM in suppressing R-loop-associated genome instability across species.

91 , we will discuss the implications for other R-loop-associated neurodegenerative diseases and point t

92 r adjacent motif (PAM) affects primarily the R-loop association rates, whereas protospacer elements d

93 es suggests that RecG is needed to dissipate R-loops at blocked replication forks.

94 We present a model that the persistence of R-loops at sites of DNA damage induces repair by break-i

95 upport a DNA repair mechanism that addresses R-loop-based DNA damage at transcriptional pause sites.

96 axin (SETX) is one of the best characterised R-loop-binding factors in vivo.

97 Further, as a result of these R-loops, both replication and transcription in the affec

98 cerevisiae RNase H2 mutant that can resolve R-loops but cannot cleave single ribonucleotides in DNA.

99 R-loops, but not normal transcription complexes, induce

100 p-mediated instability through processing of R-loops by HeLa and human neuron-like cell extracts.

101 However, reducing IgV R-loops by RNase HI overexpression in wild-type cells do

102 hosphorylate Thr-348 in the regulatory loop (R-loop) by > 10(4)-fold (k(auto) = 2.6 +/- 0.3 s(-1)).

103 Since transcriptionally-induced R-loops can occur in the absence of DNA replication, R-l

104 R-loops can trigger repeat instability at (CTG).(CAG) re

105 formation of RNA-DNA hybrids, referred to as R-loops, can promote genome instability and cancer devel

106 a rapid, global increase in the formation of R-loops, co-transcriptional RNA-DNA products, which in s

107 efficiency and the stability of the DNA-RNA (R-loop) complex structures, with a Pearson correlation c

108 R-loops comprise an RNA/DNA hybrid and a displaced singl

109 Yet the mechanisms by which R-loops compromise genome instability are poorly underst

110 transcribed, allowing for single- and double-R-loop configurations, where either or both DNA strands

111 control (modulating stability of the active R-loop conformation).

112 R-loops, consisting of an RNA-DNA hybrid and displaced s

113 Co-transcriptional R-loops could aggravate such conflicts by creating an ad

114 ocessing both substrates, but has sufficient R-loop degradation activity to complement the defects of

115 y DSBs that accumulate in response to E2 are R-loop dependent.

116 he MutLgamma (Mlh1/Mlh3) endonuclease caused R-loop-dependent CAG fragility, defining an alternative

117 NA-RNA hybrid, indicating that the effect is R-loop-dependent.

118 Antisense knockdown and R-loop destabilization both result in chromatin compacti

119 sed instability, supporting a model in which R-loops directly generate instability by aberrant proces

120 atic degradation of transcription-associated R-loops (DNA:RNA hybrids) suppresses replication fork ar

121 ro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcrip

122 These findings identify R-loops, double strand breaks and defective ATM-mediated

123 Thus, a mitosis-specific and R loop-driven ATR pathway acts at centromeres to promote

124 Disruption of this complex led to R-loop-driven DNA damage at those loci as reflected by a

125 Intriguingly, changes in R-loop dynamics have also been associated with DNA damag

126 Here, we review the causes of R-loop dysregulation in neurodegenerative diseases and h

127 egions do not appear to affect either CSR or R-loop elongation, whereas a longer (150 bp) insertion i

128 an R-loop preventing factor, is decreased at R-loop-enriched regions of IFNG and TBX21 (TH1 genes) in

129 Whether the G-density determines how far the R-loops extend is an important question.

130 t of the length over which mammalian genomic R-loops extend.

131 R loops form naturally during transcription even though

132 R loops form when transcripts hybridize to homologous DN

133 TDRD3 knockdown in cells increases R loop formation at the c-MYC locus, and Tdrd3 null mice

134 locus, and Tdrd3 null mice exhibit elevated R loop formation at this locus in B cells.

135 as a genome guardian in suppressing aberrant R-loop formation and analyse how SETX mutations can lead

136 We show that E2-dependent R-loop formation and breast cancer rearrangements are hi

137 connections and possible mechanisms linking R-loop formation and chromatin patterning.

138 nd quantify the dynamics of torque-dependent R-loop formation and dissociation for both Cascade- and

139 Double-R-loop formation and processing to instability was exten

140 eakage at expanded CAG repeats occurs due to R-loop formation and reveal two mechanisms for CAG repea

141 AM) flanking the target site, and subsequent R-loop formation and strand scission are driven by compl

142 in R-loop resolution or mutations leading to R-loop formation at specific genes affect the normal phy

143 that strengthening RNA folding and reducing R-loop formation by synonymous changes in a reporter gen

144 ur results demonstrate that interfering with R-loop formation can trigger gene activation and reveal

145 at both class switch recombination (CSR) and R-loop formation decrease significantly when the overall

146 c expression of cyclin E, G-quadruplexes, or R-loop formation facilitate the ALT pathway and lead to

147 e been reconstituted, the exact mechanism of R-loop formation has not been fully resolved.

148 stream neighbors, consistent with a role for R-loop formation in transcription termination.

149 Understanding the parameters dictating R-loop formation in vivo has been hampered by the limite

150 the first global genomic features causal for R-loop formation in yeast.

151 to investigate how conflict orientation and R-loop formation influence genome stability in human cel

152 the yeast genome, this result suggests that R-loop formation is dictated by characteristics of the D

153 ground, splicing efficiency is decreased and R-loop formation is increased in the presence of formami

154 e-H-based approach; this reveals predominant R-loop formation near gene promoters with strong G/C ske

155 R-loop formation occurs over conserved genic hotspots su

156 R-loop formation over specific, conserved, hotspots occu

157 understanding the PAM-dependent directional R-loop formation process.

158 The full R-loop formation triggers conformational changes in Casc

159 ex reveal conformational changes that enable R-loop formation with distinct positioning of each DNA s

160 ation, diffusion, site selection, reversible R-loop formation, and cleavage, using large amounts of s

161 studied the role of G-clusters in initiating R-loop formation, but we did not examine the role of G-d

162 nover at several euchromatic loci to prevent R-loop formation, ensuring proper replication progressio

163 data provide direct evidence for directional R-loop formation, starting from PAM recognition and expa

164 re often associated with promoter-associated R-loop formation.

165 Loss of H3.3 also diminishes IgV R-loop formation.

166 oviding the structural distortion needed for R-loop formation.

167 ion regions, which correspond to hotspots of R-loop formation.

168 gene structure as a critical determinant of R-loop formation.

169 displayed classical features associated with R-loop formation.

170 nscription is mutagenic, in part because the R-loop formed by the binding of the nascent RNA with its

171 this study, we found that cotranscriptional R-loops formed at a CAG-70 repeat inserted into a yeast

172 ns, and resolve deleterious DNA/RNA hybrids (R-loops) formed during transcription and RNA processing.

173 nges flanked by repetitive regions with high R-loop-forming potential.

174 Co-migration of RNase H1 and R-loops from nucleoli to perinucleolar ring structures w

175 e design of experimental strategies to probe R-loop functions.

176 e show that transcriptional RNA/DNA hybrids (R-loops) generate DNA ends that underlie stress-induced

177 how convergent transcription contributes to R-loop generation and RNA polymerase stalling.

178 e examples of diseases for which a link with R loops has been described, as well as how disease-causi

179 To determine if R-loops have a direct effect on any of the steps involve

180 usA) was rescued by ectopic expression of an R-loop-helicase UvsW, especially so on defined growth me

181 Our findings connect DNA replication to R-loop homeostasis and suggest a mechanistic basis for g

182 RNase type HI has been mainly implicated in R-loop hydrolysis, but in this study, the RNase HII doma

183 Transcriptional R-loop imbalance is a novel molecular defect causative i

184 R loops impact the genome of many organisms, regulating

185 ture that binds and unwinds dsDNA to form an R loop in which the target strand of the DNA base pairs

186 ated by RPA in vitro, fails to accumulate at R loops in cells, and loses the ability to suppress R lo

187 NaseH1 and colocalizes with both RNaseH1 and R loops in cells.

188 periphery of a transcribed locus suppressed R loops in mlp1 cells.

189 iled DNA and reduces transcription-generated R loops in vitro.

190 1 enriches in nucleoli and co-localizes with R-loops in cultured human cells.

191 ort, we demonstrate its ability to hydrolyze R-loops in Escherichia coli exposed to UV stress.

192 To characterize R-loops in fission yeast, we used the S9.6 antibody-base

193 pendent regulator of R-loop levels, reducing R-loops in the co-directional (CD) orientation but promo

194 R-loops in the switch mu region were depleted by 70% in

195 s in human cells, and can efficiently unwind R-loops in vitro.

196 To enable precision analysis of R-loops in vivo, we develop an RNase-H-based approach; t

197 ed CRISPR-Cas systems generate displacement (R-loops) in the cognate DNA sites, targeting the transpo

198 n replication-transcription conflict induces R-loops, indicating hypernegative supercoiling [(-)sc] i

199 We show that R-loops induce antisense transcription over these pause

200 This R-loop induced BIR is particularly susceptible to the fo

201 Here we demonstrate in human cells that R-loops induced by the absence of diverse RNA processing

202 Double-R-loops induced greater instability than single-R-loops.

203 leterious role for TC-NER factors in driving R-loop-induced DNA damage and genome instability.

204 tability; however, the mechanisms underlying R-loop-induced DNA damage remain unknown.

205 o implicate a (p)ppGpp synthetase protein in R-loop-induced stress response.

206 rturbation experiments further indicate that R-loop induction correlates to transcriptional pausing.

207 Yet, replication from an R-loop-initiating plasmid origin kills the double rnhAB

208 ion into duplex DNA and suggest an order for R-loop initiation and elongation in an opposite directio

209 ting that oriC-initiated replication removes R-loops instead of compounding them to R-lesions.

210 that RNase H-deficient mutants convert some R-loops into R-tracts, which progress into R-gaps and th

211 d on RNaseH1-mediated suppression of ectopic R-loops, inversely correlates with disease severity scor

212 An R-loop is a DNA:RNA hybrid formed during transcription w

213 n; it degrades RNA hybridized to DNA, so the R-loop is a potential substrate.

214 The formation of R-loops is a natural consequence of the transcription pr

215 We found the location of promoter-associated R-loops is dependent on the presence of introns.

216 Processing of the R-loops is needed to remove RNA allowing activation-indu

217 DinG, an ATP-dependent helicase that repairs R-loops, is redox-active at cellular potentials and ATP

218 Persistent R-loops lead to replicative stress due to RNA polymerase

219 H1 activity in hepatocytes showed increased R-loop levels and reduced mitochondrial encoded DNA and

220 s, suggesting that prolonged manipulation of R-loop levels could indirectly alter the transcriptome.

221 K-H loss resulted in increased basal R-loop levels, DSBs, activated DNA-damage responses and

222 cts as an orientation-dependent regulator of R-loop levels, reducing R-loops in the co-directional (C

223 strand from mu-gamma joins, indicating that R-loops limit activation-induced (cytosine) deaminase ac

224 The study proposes that cellular R-loop load could be used as a potential biomarker for m

225 strand of R-loops and obtain strand-specific R-loop maps at near nucleotide resolution.

226 The RNA of these R-loops maps to the control region of the mitochondrial

227 However, R-loops may also possess beneficial effects, as their wi

228 nsertion/deletion mutations located close to R-loop-mediated BRCA1 binding sites within TRs.

229 Thus, we identify tDNAs as a new source of R-loop-mediated DNA damage.

230 Sp deficiency provokes increased R-loops and R-loop-mediated DSBs in TH1 cells relative to TH2 cells.

231 s are the first examples to our knowledge of R-loop-mediated enhancement of gene expression involving

232 ranscribed regions, our results suggest that R-loop-mediated fragility is a mechanism that could caus

233 n fork stabilizing proteins as modulators of R-loop-mediated genome instability.

234 ese findings provide a mechanistic basis for R-loop-mediated instability at disease-associated repeat

235 We demonstrate R-loop-mediated instability through processing of R-loop

236 otic genomes have developed tools to prevent R-loop-mediated replication events that potentially cont

237 anding of how RNase HI deficiency results in R-loop-mediated transcription-replication conflict, as w

238 In most cases, R-loops occur co-transcriptionally and undergo dynamic t

239 the formation of extended RNA:DNA hybrids or R-loops or non-canonical DNA structures including G-quad

240 However, R loops persisted consistent with dual roles of K-H in t

241 Although R-loops play important roles in gene expression and reco

242 s increased, and that of topoisomerase 1, an R-loop preventing factor, is decreased at R-loop-enriche

243 mutant, revealing generation of R-lesions by R-loop-primed DNA synthesis.

244 can occur in the absence of DNA replication, R-loop processing may be a source of repeat instability

245 NA levels, suggesting impaired mitochondrial R-loop processing, transcription and mitochondrial DNA r

246 We predict that R-loops promote a chromatin architecture that defines th

247 hecin which transiently stabilized nucleolar R-loops recruited RNase H1 to the nucleoli.

248 region permanently stall, so the failure of R-loop removal in RNase H-deficient bacteria becomes let

249 epleting endogenous RNase H activity impairs R-loop removal in Saccharomyces cerevisiae, causing DNA

250 Mutations in genes involved in R-loop resolution or mutations leading to R-loop formati

251 Thus, R-loops resulting from the E2 transcriptional response a

252 ealed widespread BRCA1 binding enrichment at R-loop-rich termination regions (TRs) of actively transc

253 in vivo studies by others showing increased R-loop (RNA/DNA hybrid) formation when Sen1 activity is

254 wing cell culture systems, cotranscriptional R-loops (RNA/DNA duplex and displaced single-stranded DN

255 elements distal to the PAM affect primarily R-loop stability.

256 R-loop stabilization mediated by AtNDX inhibits COOLAIR

257 and Rrm3 binding to tDNAs is increased upon R-loop stabilization.

258 The role of this R-loop structure in positioning each DNA strand for clea

259 ed along a parallel path 25 A apart, and the R-loop structure is further stabilized by locking this s

260 sense transcription promotes formation of an R-loop structure that can be disfavored in vitro and in

261 Subsequently, the R-loop structure triggers DNA degradation.

262 no-Pozo et al. describe a connection between R loop structures and histone 3 S10 phosphorylation (H3S

263 c-Myc/Igh translocation, a process driven by R loop structures.

264 Aberrant R-loop structures are increasingly being realized as an

265 rently, it is unclear which mechanisms cause R-loop structures to become pathogenic.

266 pectedly, eRNA-expressing regions accumulate R-loop structures upon RNA exosome ablation, thus demons

267 late via the formation of co-transcriptional R-loop structures.

268 within the untranscribed strand of relevant R-loop structures.

269 on of RNase H levels did not form detectable R-loops, suggesting that prolonged manipulation of R-loo

270 RNA:DNA hybrids, plays an important role in R loop suppression.

271 rl1 protein in pre-mRNA splicing regulation, R-loop suppression and in maintaining genome stability.

272 ta describe a conserved role for Sgs1/BLM in R-loop suppression and support an increasingly broad vie

273 Most R-loops terminate within the switch repetitive zone, but

274 t transcriptional repression is caused by an R-loop that forms between the expanded repeat RNA and co

275 lytically active Streptococcus pyogenes Cas9 R-loop that show the displaced DNA strand located near t

276 Here, we show that BRCA1 is recruited to R-loops that form normally over a subset of transcriptio

277 chromatin, thereby reducing the formation of R-loops that lead to genome instability.

278 nd strand-specific identification of genuine R-loops that responded in vivo to RNase H levels and dis

279 straints lead to persistent RNA:DNA hybrids (R-loops) that prime replication in the ribosomal DNA loc

280 R-loops, three-strand structures consisting of mRNA hybr

281 R-loops, three-stranded structures that form when transc

282 ability has been explained by the ability of R-loops to induce DNA damage.

283 The possible contribution of aberrant R-loops to pathological conditions is also discussed.

284 reducing negative supercoiling and resolving R loops, TOP3B promotes transcription, protects against

285 R-loops, transcriptionally-induced RNA:DNA hybrids, occu

286 or B cell lines, the upstream boundaries of R-loops typically begin early in the repetitive portion

287 We profiled R-loops using a high-resolution, strand-specific methodo

288 R-loop accumulation, and the accumulation of R-loops was exacerbated when both proteins were depleted

289 sm by which eukaryotic cells prevent harmful R loops, we used human activation-induced cytidine deami

290 ing or repairing damage caused by stabilized R loops were identified.

291 R-loops were further elevated upon deletion of yeast RNa

292 iation from oriK depends on RNA-DNA hybrids (R-loops), which are normally removed by enzymes such as

293 to the formation of stable RNA-DNA hybrids (R-loops), which inhibit successive rounds of transcripti

294 the mRNA may hybridize with DNA, forming an R loop, which can be physiological or pathological, cons

295 R loops, which are mainly co-transcriptional, abundant R

296 ly drives a conformational transition of the R-loop, which is essential for efficient substrate phosp

297 at nrl1Delta cells accumulate high levels of R-loops, which co-localize with HR repair factors and re

298 R-loops, which result from the formation of stable DNA:R

299 ese helicases is suppressed by destabilizing R-loops while Pif1 and Rrm3 binding to tDNAs is increase

300 cognition by forming a site-specific hybrid (R-loop) with its complement (protospacer) on an invading