ライフサイエンスコーパス: MRX

1 MRX also stimulates recruitment of Exo1 and antagonizes

2 MRX is required to tether transcriptionally active loci

3 MRX restricts transcription of coding and noncoding DNA

4 ently whenever intravenously infused MBs (3% MRX-801; NuVox) were visualized near the thrombus (n = 1

5 1 cells are not exacerbated by the loss of a MRX protein.

6 light the crucial role of Sae2 in activating MRX cleavage at the correct cell cycle stage.

7 nd form of Rad50, which is essential for all MRX-dependent activities.

8 re the role of MRX at telomeres, we analyzed MRX mutants in a de novo telomere addition assay in yeas

9 Here we demonstrate that dsDNA and MRX activate Tel1 synergistically.

10 ase IV appeared at the DSB later than Ku and MRX and in a strongly Ku-dependent manner.

11 Results revealed that Ku and MRX assembled at a DSB independently and rapidly after D

12 ified enzymes in vitro, we found that Ku and MRX regulate the nuclease activity of Exo1 in an opposit

13 lomere and recombination functions of Ku and MRX, confirming that these protein regions are functiona

14 ereas the diploid mutants use the Rad52- and MRX-dependent pathways that repair double strand breaks.

15 We suggest that Top3-Rmi1 and MRX are important for recruitment of the Sgs1-Dna2 compl

16 n a manner that is enhanced by Top3-Rmi1 and MRX.

17 Tel1p, appears to act in the same pathway as MRX: mec1 tel1 cells have telomere phenotypes similar to

18 nhances ATP hydrolysis by MRX and attenuates MRX function in end-tethering, suggesting that Rif2 can

19 feasibility of immunoassays using GMR-based MRX and provides an alternative platform for point-of-ca

20 and the ratio-dependent interaction between MRX-2843 and vincristine significantly impacted therapeu

21 o found that Rif2 enhances ATP hydrolysis by MRX and attenuates MRX function in end-tethering, sugges

22 ity profile that is preferentially nicked by MRX.

23 but facilitates endonucleolytic scission by MRX with a dependence on ATP and Sae2.

24 ever, the mechanism of activation of Tel1 by MRX remains unclear, as does the role of effector DNA.

25 otein complexes in Saccharomyces cerevisiae: MRX (Mre11-Rad50-Xrs2), Ku (Ku70-Ku80), and DNA ligase I

26 imizes the therapeutic potential of combined MRX-2843 and vincristine in T-ALL and describe a novel t

27 d53 (Chk2) and recombination protein complex MRX(MRN) inhibit Exo1 in one pathway, whereas in a secon

28 The MRN complex (MRX in Saccharomyces cerevisiae, made of Mre11, Rad50 an

29 The MRN complex (MRX in yeast) has a direct role in DSB repair and is als

30 sDNA and the Mre11-Rad50-Xrs2(NBS1) complex (MRX).

31 In yeast, the Mre11-Rad50-Xrs2 complex (MRX) collaborates with Sae2 to initiate DSB repair.

32 i1 complex and the Mre11-Rad50-Xrs2 complex (MRX) have important roles as stimulatory components.

33 We show that the Mre11-Rad50-Xrs2 complex (MRX) initiates 5' degradation, whereas Sgs1 and Dna2 deg

34 ves nicking by the Mre11-Rad50-Xrs2 complex (MRX), then exonucleolytic digestion by Exo1.

35 In contrast, nanoparticles containing MRX-2843 alone were ineffective in this model.

36 ing of both Tbf1 and Rap1 proteins decreases MRX and Tel1 accumulation at nearby DNA ends.

37 Once Tel1 is delocalized, MRX does not associate efficiently with Rap1-covered DNA

38 -C47, that causes a defect in Sae2-dependent MRX 3'-5' exonuclease activity, but not endonuclease act

39 for the first time, a GMR-based time-domain MRX bioassay.

40 , we systematically investigated time-domain MRX by measuring the signal dependence on the applied fi

41 vement in uls1Delta correlates with elevated MRX and cohesin loading, despite normal resection and ch

42 Here, we report a new function for MRX in limiting transcription in budding yeast.

43 e brain and is a suitable candidate gene for MRX.

44 In the absence of NHEJ and a functional MRX/N, meiotic DSBs are channeled to EXO-1-dependent HR

45 n of Tel1(ATM) depends on the heterotrimeric MRX(MRN) complex, composed of Mre11, Rad50, and Xrs2 (hu

46 How MRX-DNA interactions support 5' strand-specific nicking

47 We present models for how MRX-Sae2 creates entry sites for the long-range resectio

48 The results provide new insights into how MRX catalyses end resection and recombination initiation

49 We identify MRX (Mre11-Rad50-Xrs2) as a positive regulator of this i

50 nucleosomes as well as transcription impeded MRX incisions.

51 In MRX, the magnetic nanoparticles (MNPs) are first magneti

52 y, abolition of this exonuclease activity in MRX mutants results in shortened telomeric DNA tracts.

53 ted degradation of DSB ends occurred even in MRX mutants with persistently bound Ku.

54 Excitingly, the TAM kinase inhibitor MRX-2843 currently in human clinical trials to treat AML

55 ubtelomere-binding protein Tbf1 and inhibits MRX localization to DNA ends.

56 collaborates with Rif1 and Rif2 and inhibits MRX localization to DNA ends.

57 hering of Fab fragments to DNA ends inhibits MRX-mediated DNA end processing but enhances Tel1 activa

58 activation assay, we show that Rif2 inhibits MRX-dependent Tel1 kinase activity.

59 short telomeric TG repeat sequence inhibits MRX accumulation at nearby DNA ends in a Tbf1-dependent

60 d DSBs depended on the presence of an intact MRX complex and ATP binding by Rad50, suggesting a possi

61 t insight into how mutations in a Rho-linked MRX gene may compromise neuronal function.

62 Magnetorelaxometry (MRX) is a promising new biosensing technique for point-o

63 ing a deep sequencing-based assay, we mapped MRX nicks at single-nucleotide resolution next to multip

64 patients with ALGS treated with maralixibat (MRX), an ileal bile acid transporter inhibitor.

65 Moreover, MRX-mediated chromatin anchoring to the NPC contributes

66 The Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex orchestrates the cellular response to DSB

67 The Mre11-Rad50-Xrs2/NBS1 (MRX/N) nuclease/ATPase complex plays structural and cata

68 rent mechanisms, ensuring diverse actions of MRX-Sae2 nuclease at DNA ends.

69 to a DNA gap via the exonuclease activity of MRX, which is stimulated by Sae2 without ATP being prese

70 itive particles, containing a higher dose of MRX-2843, provided more effective disease control than t

71 The median duration of MRX was 4.7 years (IQR: 1.6-5.8); 16 had events (10 LT,

72 ition to promote the 3' -> 5' exonuclease of MRX, which requires ATP hydrolysis by Rad50.

73 nt of MRX to the DSB, and other functions of MRX in HR including the recruitment of long-range resect

74 NF orchestrates the recruitment of a pool of MRX that is specifically dedicated to HR.

75 aining an even higher, antagonistic ratio of MRX-2843 and vincristine were less effective.

76 on is accompanied by impaired recruitment of MRX to the DSB, and other functions of MRX in HR includi

77 To further explore the role of MRX at telomeres, we analyzed MRX mutants in a de novo t

78 ding by Rad50, suggesting a possible role of MRX in terminating a NHEJ repair phase.

79 ination assay in yeast to assess the role of MRX in V(D)J joining.

80 es a model of how the individual subunits of MRX and DNA regulate Tel1 kinase activity.

81 al fragment of Rev7 binds to the subunits of MRX complex, protects rev7Delta cells from G-quadruplex

82 patients with ALGS from 3 clinical trials of MRX with up to 6 years of follow-up.

83 ropyridin -1(2H)-yl)phenyl)oxazolidin-2-one (MRX-I), distinguished by its high activity against Gram-

84 ovide a model that indicates how in Rad53 or MRX mutants, an inappropriately active Exo1 may facilita

85 X-106 (pan-TAM), ASP-2215 (Axl specific), or MRX-2843 (Mertk specific) showed enhanced mineralization

86 We find that the ability of Sae2 to promote MRX nuclease functions is important for DNA damage survi

87 These data indicate that Tel1 promotes MRX retention to DSBs and this function is important to

88 The role of Tel1 in promoting MRX accumulation to DSBs is counteracted by Rif2, which

89 d this function is important to allow proper MRX-DNA binding that is needed for end-tethering and DSB

90 ix individuals met the criteria of receiving MRX for >=48 weeks with laboratory values available at w

91 e and endonuclease activities of recombinant MRX-Sae2 preferentially degrade the 5'-terminated DNA st

92 tethering, suggesting that Rif2 can regulate MRX activity at DSBs by modulating ATP-dependent conform

93 ected DSB-proximal nicks and that repetitive MRX cleavage extended the length of resection tracts.

94 Nonsyndromic X-linked mental retardation (MRX) syndromes are clinically homogeneous but geneticall

95 in nonspecific X-linked mental retardation (MRX), three encode regulators or effectors of the Rho GT

96 n implicated in X-linked mental retardation (MRX).

97 The DNA damage sensor MRX is required for histone loss, which also depends on

98 ncluding Ku, RPA, and nucleosomes, stimulate MRX-Sae2 endonuclease cleavage in vitro.

99 and computational approaches, we found that MRX-2843 synergized strongly-and in a ratio-dependent ma

100 Together, these findings indicate that MRX has a role in transcription and chromosome organizat

101 and EGFRMT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinic

102 We show that MRX interacts physically and colocalizes on chromatin wi

103 We show that MRX is disabled by telomeric protein Rif2 through an N-t

104 Here, we show that MRX recruits Dna2 nuclease to DSB ends.

105 the absence of histone loss, suggesting that MRX-dependent nucleosome remodelling regulates the acces

106 We also uncovered that MRX-Sae2 endonuclease introduces a cleavage at defined d

107 section by the Top3-Rmi1 heterodimer and the MRX proteins is by complex formation with Sgs1, which un

108 into the functional interaction between the MRX subunits and Rev7 and highlight a previously unrecog

109 We infer that Fun30 promotes both the MRX- and Exo1-dependent steps in resection, possibly by

110 1(ATM) can be recruited and activated by the MRX complex, resulting in telomere elongation.

111 uired to inhibit telomere degradation by the MRX complex.

112 ble-strand breaks (DSBs) is initiated by the MRX/MRN complex (Mre11-Rad50-Xrs2 in yeast; Mre11-Rad50-

113 nd Xrs2p proteins form a complex, called the MRX complex, that is required to maintain telomere lengt

114 Rad50 and Xrs2 proteins and thereby for the MRX complex in promoting PRR via both the Rad5 and Rad52

115 n, we showed an absolute requirement for the MRX complex in signal joining, suggesting that the Mre11

116 nd protection by Ku, the requirement for the MRX complex is bypassed and resection is executed by Exo

117 In Caenorhabditis elegans, evidence for the MRX/N role in DSB resection is limited.

118 olecular events leading to a switch from the MRX/Sae2-dependent initiation to the Exo1- and Dna2-depe

119 Several proteins, including the MRX/N complex, Tel1/ATM (ataxia telangiectasia mutated),

120 DNA repair through a mechanism involving the MRX complex, a major player in DNA double strand break r

121 In exo1Deltasgs1Delta double mutants, the MRX complex together with Sae2 nuclease generate, in a s

122 Here we report that loss of the MRX (Mre11p, Rad50p, Xrs2p) and Ku70/80 (Ku70p, Ku80p) c

123 In contrast, Mre11 protein, part of the MRX complex, accumulates at unresected DSB ends.

124 Among these were subunits of the MRX complex, which forms a molecular structure similar t

125 for the telomerase-promoting activity of the MRX complex.

126 Mre11 is one member of the MRX/N (Mre11, Rad50, and Xrs2/Nbs1) complex required for

127 11-Rad50-Xrs2 (MRX) complex and preceded the MRX-dependent broad eviction of histones and DNA end-res

128 vated ATP-bound state, thereby rendering the MRX complex incompetent for Tel1 activation.

129 indings demonstrate that Sae2 stimulates the MRX endo- and exonuclease activities via Rad50 by differ

130 sphorylated Sae2, along with stimulating the MRX endonuclease as shown previously, also overcomes thi

131 letions arise in yeast, and suggest that the MRX and Ku70/80 complexes are partially redundant in mit

132 Further investigation indicated that the MRX complex did not contribute to metaphase cohesion ind

133 from this model system, we propose that the MRX complex helps to prepare telomeric DNA for the loadi

134 Rather, the data suggest that the MRX complex is involved in recruiting telomerase activit

135 We found that the MRX genes were absolutely required for telomerase-mediat

136 ng in the absence of Ku and Sae2 or when the MRX complex is intact, but functionally compromised by e

137 These data rule out models in which the MRX complex is necessary for Cdc13p binding to telomeres

138 Cdc13p binding to telomeres or in which the MRX complex is necessary for the catalytic activity of t

139 l1 is activated through interaction with the MRX complex and DNA ends.

140 e revealed all known interactions within the MRX, Ku, and DNA ligase IV complexes, as well as three a

141 s of Mre11 functionally integrate within the MRX-Sae2 ensemble to resect 5'-terminated DNA.

142 Cells lacking any one of the three MRX proteins and Mec1p, an ATM-like protein kinase, unde

143 Each of the three MRX subunits shows a physical association with Tel1.

144 Thus, MRX may regulate two pathways of chromatin changes: nucl

145 Thus, MRX-2843 increased the sensitivity of ETP-ALL cells to v

146 at the MR complex has equivalent activity to MRX in cleavage of protein-blocked DNA ends.

147 r, how mutations in Rho-linked genes lead to MRX.

148 ctionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired depend

149 or palindromic DNA structure susceptible to MRX-Sae2, and internal protein blocks also trigger DNA c

150 Sae2 stimulates two MRX nuclease activities, endonuclease and 3'-5' exonucle

151 -stranded DNA in vitro relative to wild-type MRX, consistent with the increased turnover of Mre11 fro

152 In vivo, MRX is required for a 5' --> 3' exonuclease activity tha

153 These results support a model in which MRX controls Tel1 activation by recognizing protein-boun

154 Our results support a model in which MRX-Sae2 catalyzes 5'-DNA end degradation by stepwise en

155 ein that is absent in a family affected with MRX, is required for dendritic spine morphogenesis.

156 charomyces cerevisiae Sae2 can function with MRX to initiate 5'-3' end resection and also plays an im

157 synergize in a lineage-specific manner with MRX-2843, a small molecule dual MERTK and FLT3 kinase in

158 ted individuals in a multiplex pedigree with MRX (MRX30), previously mapped to Xq22, show a point mut

159 n primary T-ALL patient samples treated with MRX-2843 and vincristine nanoparticle formulations, sugg

160 e progression for ALGS patients treated with MRX.

161 Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, pro

162 Indeed, treatment with MRX-2843, a first-in-class MERTK kinase inhibitor, resen

163 uggest that MIN promotes a transition within MRX that is not conductive for endonuclease activity, DN

164 dent of the end-processing Mre11-Rad50-Xrs2 (MRX) complex and preceded the MRX-dependent broad evicti

165 The budding yeast Mre11-Rad50-Xrs2 (MRX) complex and Sae2 function together in DNA end resec

166 The yeast Mre11-Rad50-Xrs2 (MRX) complex and Sae2 function together to initiate DNA

167 joining component, and the Mre11-Rad50-Xrs2 (MRX) complex and Sae2, end-processing factors crucial fo

168 In budding yeast, the Mre11-Rad50-Xrs2 (MRX) complex associates with DNA ends and promotes check

169 In yeast, the Mre11-Rad50-Xrs2 (MRX) complex nicks 5'-terminated DSB ends to initiate nu

170 iated by the action of the Mre11-Rad50-Xrs2 (MRX) complex to direct repair toward HR.

171 e Saccharomyces cerevisiae Mre11-Rad50-Xrs2 (MRX) complex, the Sgs1-Top3-Rmi1 complex, Dna2 protein a

172 ation of Tel1, but not the Mre11-Rad50-Xrs2 (MRX) complex, to adjacent DNA ends.

173 inding at DNA ends via the Mre11-Rad50-Xrs2 (MRX) complex.

174 Mre11-Rad50-Xrs2 (MRX) is a highly conserved complex with key roles in var

175 sically interacts with the Mre11-Rad50-Xrs2 (MRX) subunits, impedes G-quadruplex DNA synergized HU-in

176 ge response by controlling Mre11-Rad50-Xrs2 (MRX)-catalyzed end resection, an essential step for homo

177 -Nej1 (DNA ligase IV), and Mre11-Rad50-Xrs2 (MRX).

178 requires several enzymes; Mre11/Rad50/Xrs2 (MRX) and Sae2 are implicated in the onset of 5'-strand r

179 k restart pathway, and the MRE11/RAD50/XRS2 (MRX) complex were critical for viability of rrm3 cells.

180 e of Sae2 is linked to the Mre11/Rad50/Xrs2 (MRX) complex, which is important for the processing of D

181 n, Ku, and the HR protein, Mre11/Rad50/Xrs2 (MRX) complex.

182 nents of the homologous Mre11p-Rad50p-Xrs2p (MRX) complex are viable.

183 accharomyces cerevisiae Mre11p/Rad50p/Xrs2p (MRX) complex is evolutionarily conserved and functions i

184 erevisiae: the Ku heterodimer (Yku70-Yku80), MRX (Mre11-Rad50-Xrs2), and DNA ligase IV (Dnl4-Lif1), a