ライフサイエンスコーパス: MCM2

1 1) and minichromosome maintenance protein 2 (mcm2).

2 ective in stimulating DDK phosphorylation of Mcm2.

3 forks and interacts transiently with phospho-MCM2.

4 nished stimulation of DDK phosphorylation of Mcm2.

5 saccharide fold (OB-fold) and A subdomain of Mcm2.

6 ells, with diminished DDK phosphorylation of Mcm2.

7 A family of six homologous subunits, Mcm2, -3, -4, -5, -6, and -7, each with its own unique f

8 e show that Cdt1 interacts with MCM subunits Mcm2, 4 and 6, which both destabilizes the Mcm2-5 interf

9 izes MCM in a left-handed spiral open at the Mcm2-5 gate.

10 s Mcm2, 4 and 6, which both destabilizes the Mcm2-5 interface and inhibits MCM ATPase activity.

11 to either ATPgammaS or ADP, whereas the apo MCM2-5 interface remains open.

12 The consequences of inappropriate Mcm2/5 gate actuation and the role of a side channel for

13 The gate-distinct from that between Mcm2/5 used for origin loading-is intrinsic to CMG; howe

14 Recent cryo-EM structures of the Mcm2-7 (MCM) double hexamer, its precursors, and the ori

15 ing a prereplication complex that contains a Mcm2-7 (minichromosome maintenance proteins 2-7) double

16 the eukaryotic DNA replicative helicase, the Mcm2-7 (minichromosome maintenance) complex, is loaded a

17 rom structure of S. cerevisiae ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) bound to origin DNA revealed that a loop w

18 A key intermediate is the ORC-Cdc6-Cdt1-Mcm2-7 (OCCM) complex in which DNA has been already inse

19 e origin recognition complex (ORC)-Cdc6-Cdt1-Mcm2-7 (OCCM) intermediate showed that each of these sub

20 ial' complex is transformed into an ORC/Cdc6/MCM2-7 (OCM) complex.

21 nded (ss) DNA are bound within the C-tier of MCM2-7 AAA+ ATPase domains.

22 Although Mcm2-7 activation requires binding of the helicase-activ

23 activity was required for maximal loading of Mcm2-7 and a dramatic genome-wide reorganization of the

24 eplicate with decreased chromatin loading of MCM2-7 and become critically dependent on another ATPase

25 lication fork helicase is composed of Cdc45, Mcm2-7 and GINS (CMG).

26 replicative CMG helicase (comprising CDC45, MCM2-7 and GINS) occurs only after the final ligation st

27 tive DNA helicase CMG (the complex of CDC45, MCM2-7 and GINS).

28 ation as a ring-shaped heterohexamer to load MCM2-7 and initiate DNA replication.

29 leted cells show normal chromatin binding of MCM2-7 and initiate replication from a similar number of

30 f mini chromosome maintenance (MCM) proteins MCM2-7 and PARP and named this the mtp53-PARP-MCM axis.

31 0 stabilizes Cdc45 and GINS association with Mcm2-7 and stimulates replication elongation in vivo and

32 rom budding yeast, that Dpb11 alone binds to Mcm2-7 and that Dpb11 also competes with GINS for bindin

33 nd MSSB mutant combinations in S. cerevisiae Mcm2-7 are not viable.

34 re, origin melting and GINS association with Mcm2-7 are substantially decreased for cells expressing

35 or double-hexamer formation following second Mcm2-7 association, suggesting that this process is faci

36 xes containing ATPase-motif mutations showed Mcm2-7 ATP binding and hydrolysis are required for helic

37 ic structure, our findings show that the six Mcm2-7 ATPase active sites are specialized for different

38 ic DNA replication is the recruitment of the MCM2-7 ATPase, the core of the replicative DNA helicase,

39 A subset of Mcm2-7 ATPase-site mutants completed helicase loading bu

40 Sld2-m1,4, that is specifically defective in Mcm2-7 binding.

41 for intermediates consisting of an ORC-Cdc6-Mcm2-7 complex and an ORC-Cdc6-Mcm2-7-Mcm2-7 complex are

42 east, that Mcm10 directly interacts with the Mcm2-7 complex and Cdc45.

43 e complex protein Mcm4 alone and also of the Mcm2-7 complex and the dsDNA-loaded Mcm2-7 complex.

44 C-Cdc6-Mcm2-7 complex and an ORC-Cdc6-Mcm2-7-Mcm2-7 complex are reported, which together provide new

45 After Cdc45-Mcm2-7 complex assembly, Mcm10 promotes origin melting b

46 n origins prior to Cdt1 release and ORC-Cdc6-Mcm2-7 complex formation, but how the second Mcm2-7 hexa

47 ave other roles, the essential nature of the MCM2-7 complex in DNA replication has made it difficult

48 ulating the assembly and distribution of the Mcm2-7 complex in the Drosophila genome.

49 In fact, Mcm10 recruits Cdc45 to Mcm2-7 complex in vitro.

50 uitment of Cdc45 and GINS recruitment to the Mcm2-7 complex in vivo during early S phase.

51 complex, but not the 'initial' ORC/Cdc6/Cdt1/MCM2-7 complex, is competent for MCM2-7 dimerization.

52 eukaryotic replisome components include the Mcm2-7 complex, the CMG helicase, DNA polymerases, a Ctf

53 o of the Mcm2-7 complex and the dsDNA-loaded Mcm2-7 complex.

54 nished GINS and pol-alpha recruitment to the Mcm2-7 complex.

55 tes are on predicted exposed surfaces of the MCM2-7 complex.

56 involved in the recruitment of Cdc45 to the Mcm2-7 complex.

57 pendent fashion with kinetics similar to the MCM2-7 complex.

58 7 hexamer to form an 'initial' ORC/Cdc6/Cdt1/MCM2-7 complex.

59 th RNA polymerase induce a redistribution of Mcm2-7 complexes along the chromosomes, resulting in a c

60 Mutant Mcm2-7 complexes assemble and are recruited to replicati

61 ential Mcm4 motif that permit loading of two Mcm2-7 complexes but are defective for double-hexamer fo

62 Mcm2-7 complexes containing ATPase-motif mutations showe

63 These excess Mcm2-7 complexes exhibit little co-localization with ORC

64 mplexes (pre-RCs) license origins by loading Mcm2-7 complexes in inactive form around DNA.

65 n complex (ORC) assemble two heterohexameric Mcm2-7 complexes into a head-to-head double hexamer that

66 licase loading but instead drives removal of Mcm2-7 complexes that cannot complete loading.

67 e result of sequential loading of individual Mcm2-7 complexes.

68 ion are still debated, it interacts with the Mcm2-7 core helicase, the lagging strand polymerase, DNA

69 Here, we report the cryo-EM structure of the Mcm2-7 DH on dsDNA and show that the DNA is zigzagged in

70 To convert the Mcm2-7 DH structure into the Mcm2-7 hexamer structure fo

71 The MCM2-7 dimer, in contrast to the MCM2-7 double-hexamer,

72 s competent for MCM2-7 dimerization, reveals MCM2-7 dimerization as a limiting step during pre-RC for

73 identifies the OCM complex as competent for MCM2-7 dimerization, reveals MCM2-7 dimerization as a li

74 utants we discovered a complex competent for MCM2-7 dimerization.

75 C/Cdc6/Cdt1/MCM2-7 complex, is competent for MCM2-7 dimerization.

76 se, replisomes assemble around the activated Mcm2-7 DNA helicase.

77 In "pre-insertion OCCM," the main body of Mcm2-7 docks onto ORC-Cdc6, and the origin DNA is bent a

78 tin environment restricts the loading of the Mcm2-7 double hexamer either upstream of or downstream f

79 py, we report a near-atomic structure of the MCM2-7 double hexamer purified from yeast G1 chromatin.

80 uding RNA polymerase, can push budding yeast Mcm2-7 double hexamers along DNA.

81 eplication origins are "licensed" by loading MCM2-7 double hexamers and during S phase licensed repli

82 These experiments indicate that Mcm2-7 double hexamers can be precursors of replication

83 dictate Mcm2-7 loading specificity and that Mcm2-7 double hexamers form preferentially at a native o

84 Displaced Mcm2-7 double hexamers support DNA replication initiatio

85 ecruitment of Dbf4-dependent kinase (DDK) to Mcm2-7 double hexamers, which in turn promotes DDK phosp

86 point kinase, Rad53, inhibits DDK binding to Mcm2-7 double hexamers.

87 nize and encircle origin DNA and assemble an Mcm2-7 double-hexamer around adjacent double-stranded DN

88 RC) assembly after OCM formation, but before MCM2-7 double-hexamer assembly.

89 Detailed structural analysis of the loaded Mcm2-7 double-hexamer complex demonstrates that the two

90 ly is inhibited, which is unexpected, as the MCM2-7 double-hexamer represents a very large interactio

91 The MCM2-7 dimer, in contrast to the MCM2-7 double-hexamer, interacts with ORC/Cdc6 and is sa

92 how the OCM is subsequently converted into a MCM2-7 double-hexamer.

93 eplicative complexes (pre-RCs), resulting in MCM2-7 double-hexamers on DNA.

94 ring S phase, impaired GINS interaction with Mcm2-7 during S phase, and decreased replication protein

95 s in increased interaction between Dpb11 and Mcm2-7 during S phase, impaired GINS interaction with Mc

96 kedly disrupted interaction between GINS and Mcm2-7 during S phase.

97 KEAP1 is thus poised to affect MCM2-7 dynamics or function rather than MCM3 abundance.

98 Single-molecule studies show mutant Mcm2-7 forms initial hexamer-hexamer interactions; howev

99 interaction could provide key insights into Mcm2-7 function and regulation.

100 The replicative helicase Mcm2-7 functions in both initiation and fork progression

101 The MCM2-7 genes are coordinately expressed during developme

102 Overexpression of MCM2-7 genes correlated with poor prognosis in breast ca

103 ntly correlated with an increasing number of MCM2-7 genes overexpression.

104 heterozygous loss or mutation of one or more MCM2-7 genes, which is expected to compromise DNA replic

105 inding experiments confirmed that CMG and/or Mcm2-7 had to be phosphorylated for binding to phospho-T

106 Furthermore, dsDNA-loaded Mcm2-7 harboring the DDK phosphomimetic Mcm4 mutant boun

107 g G1-phase of the cell-cycle the replicative MCM2-7 helicase becomes loaded onto DNA into pre-replica

108 Cdc45) and GINS proteins activate the latent Mcm2-7 helicase by inducing allosteric changes through b

109 defined by the ORC-dependent loading of the Mcm2-7 helicase complex onto chromatin in G1.

110 sence of FACT during replication stress, the MCM2-7 helicase dissociates from chromatin, resulting in

111 d into two biochemically discrete steps: the Mcm2-7 helicase is first loaded into prereplicative comp

112 recognition complex (ORC), which coordinates Mcm2-7 helicase loading to form the prereplicative compl

113 that mTOR signaling promotes the loading of MCM2-7 helicase onto chromatin and upregulates DNA repli

114 eaction and, with the help of Cdt1, the core Mcm2-7 helicase onto DNA.

115 oading, but also for the distribution of the Mcm2-7 helicase prior to S-phase entry.

116 This origin licensing requires loading two Mcm2-7 helicases around origin DNA in a head-to-head ori

117 s ORC-Cdc6 function to recruit a single Cdt1-Mcm2-7 heptamer to replication origins prior to Cdt1 rel

118 The Mcm2-7 heterohexamer, like other hexameric helicases, is

119 g yeast is the association of Cdc45 with the Mcm2-7 heterohexameric ATPase, and a second step is the

120 establish that the Saccharomyces cerevisiae MCM2-7 hexamer assumes a closed ring structure, suggesti

121 During S phase, each Mcm2-7 hexamer forms the core of a replicative DNA helic

122 the active helicase, the N-tier ring of the Mcm2-7 hexamer in the DH-dsDNA needs to tilt and shift l

123 tch onto ORC-Cdc6 while the main body of the Mcm2-7 hexamer is not connected.

124 Mcm2-7 complex formation, but how the second Mcm2-7 hexamer is recruited to promote double-hexamer fo

125 To convert the Mcm2-7 DH structure into the Mcm2-7 hexamer structure found in the active helicase, t

126 Cdc6 recruits with the help of Cdt1 a single MCM2-7 hexamer to form an 'initial' ORC/Cdc6/Cdt1/MCM2-7

127 Through analysis of MCM2-7 hexamer-interface mutants we discovered a complex

128 tion, the core component of the helicase-the Mcm2-7 hexamer-is loaded on origin DNA as a double hexam

129 ents a specific conformational change in the Mcm2-7 hexamer.

130 is guided by ORC-Cdc6 and inserted into the Mcm2-7 hexamer.

131 dc45, Mcm2-7, GINS) helicase consists of the Mcm2-7 hexameric ring along with five accessory factors.

132 n complex (ORC), Cdc6, and Cdt1 assemble two MCM2-7 hexamers into one double hexamer around dsDNA.

133 Finally, we demonstrate that single Mcm2-7 hexamers propagate bidirectionally, monotonically

134 it, even its ATPase subunit, can load enough MCM2-7 in partnership with CDC6 to initiate DNA replicat

135 e BRCT4 motif of Dpb11 that remains bound to Mcm2-7 in the presence of ssDNA (dpb11-m1,m2,m3,m5), and

136 ucleotide ssDNA, and recruiting pol alpha to Mcm2-7 in vitro.

137 o, Ichi, Ni, and San (GINS) association with Mcm2-7 in vivo.

138 o test this model and assess the location of Mcm2-7 initial loading, we placed DNA-protein roadblocks

139 Thus, the origin melting and GINS-Mcm2-7 interaction defects we observed for mcm10-m2,3,4

140 However, while eukaryotic MCM2-7 is a heterocomplex made of different polypeptide

141 MCM2-7 is activated by both the CDC7-Dbf4 kinase and cyc

142 ve helicase to the replication origin, where MCM2-7 is activated to initiate DNA replication.

143 These data suggest that Sld2 binding to Mcm2-7 is essential to block the inappropriate formation

144 The minimal amounts of Mcm2-7 loaded in the absence of cyclin E/Cdk2 activity w

145 deling by ORC, and that DNA bending promotes Mcm2-7 loading in vitro.

146 h DNA geometry and bendability contribute to Mcm2-7 loading site selection in metazoans.

147 dynamics of the ORC-Cdc6 interaction dictate Mcm2-7 loading specificity and that Mcm2-7 double hexame

148 er the course of G1 is not only critical for Mcm2-7 loading, but also for the distribution of the Mcm

149 uitment, initiator-specific co-assembly, and Mcm2-7 loading.

150 Loading of each Mcm2-7 molecule involves the ordered association and dis

151 MG (Cdc45, Mcm2-7, GINS) helicase contains a Mcm2-7 motor ring, with the N-tier ring in front and the

152 Loading-defective Mcm2-7 mutant complexes were defective in initial Mcm2-7

153 a detailed analysis of Arabidopsis thaliana mcm2-7 mutants and reveal phenotypic differences.

154 We demonstrate that these MCM2-7 mutants arrest during prereplicative complex (pre

155 Yet the double mutant cells grow, recruit MCM2-7 normally to chromatin, and initiate DNA replicati

156 he loaded conformers in which the loading of Mcm2-7 on DNA is complete and the DNA entry gate is full

157 ndependent, CDC6-dependent mechanism to load MCM2-7 on origins of replication.

158 al how ORC, Cdc6, and Cdt1 cooperate to load MCM2-7 onto DNA, enabling bidirectional replication.

159 or mutations that bypass the requirement for Mcm2-7 phosphorylation by DDK restored PFA in the absenc

160 Here we show that TIM interacts with MCM2-7 prior to the initiation of DNA replication.

161 Contrary to the sites of Mcm2-7 recruitment being precisely defined, only single

162 7 mutant complexes were defective in initial Mcm2-7 recruitment or Cdt1 release.

163 Paradoxically, there is a vast excess of Mcm2-7 relative to ORC assembled onto chromatin in G1.

164 s a 10-fold decrease in chromatin-associated Mcm2-7 relative to the levels found at the G1/S transiti

165 in CHK1 checkpoint activation and decreased MCM2-7 replication helicase and PCNA associated with chr

166 Activation of the Mcm2-7 replicative DNA helicase is the committed step in

167 tiate DNA replication by phosphorylating the Mcm2-7 replicative helicase [5-7].

168 Loading of the ring-shaped Mcm2-7 replicative helicase around DNA licenses eukaryot

169 ase active site (mcm2DENQ), we show that the Mcm2-7 replicative helicase has a novel DRC function as

170 ORC), Cdc6, and Cdt1 co-assemble to load the Mcm2-7 replicative helicase onto chromatin.

171 x (ORC), a DNA-binding ATPase that loads the Mcm2-7 replicative helicase onto replication origins.

172 on requires DNA loading of two copies of the Mcm2-7 replicative helicase to form a head-to-head doubl

173 plication licensing factor CDC6 recruits the MCM2-7 replicative helicase to the replication origin, w

174 e MCM8-9 complex, which is paralogous to the MCM2-7 replicative helicase.

175 single-molecule FRET, arrival of the second Mcm2-7 results in rapid double-hexamer formation that an

176 Kinetic analyses of wild-type and mutant Mcm2-7 reveal a limited time window for double-hexamer f

177 f4-Cdc7 phosphorylation of Mcm2 may open the Mcm2-7 ring at the Mcm2-Mcm5 interface, allowing for sin

178 between GINS/Cdc45 and the outer edge of the Mcm2-7 ring for unwinding have remained unexplored.

179 d Dbf4-Cdc7 phosphorylation of Mcm2 promotes Mcm2-7 ring opening.

180 ed in the interface between these domains in Mcm2-7 structures, mutations predicted to separate the d

181 The Mcm2-7 subcomplex forms a cracked-ring, right-handed spi

182 his study demonstrates the importance of the MCM2-7 subunits during seed development and suggests tha

183 eukaryotes, the MSSB is conserved in several Mcm2-7 subunits, and MSSB mutant combinations in S. cere

184 e-wide reorganization of the distribution of Mcm2-7 that is shaped by active transcription.

185 on the chromatin can recruit and load enough MCM2-7 to initiate DNA replication, or human cell lines

186 n, or human cell lines can sometimes recruit MCM2-7 to origins independent of ORC.

187 trusion of ssDNA from the central channel of Mcm2-7 triggers GINS attachment to Mcm2-7.

188 ld3/Treslin coordinates Cdc45 recruitment to Mcm2-7 with DDK phosphorylation of Mcm2 during S phase.

189 uble hexamers of minichromosome maintenance (Mcm2-7) at origin sites.

190 engage the mini-chromosome maintenance 2-7 (MCM2-7) complex during replicative helicase loading; how

191 The MINICHROMOSOME MAINTENANCE 2-7 (MCM2-7) complex, a ring-shaped heterohexamer, unwinds th

192 heterohexameric minichromosome maintenance (MCM2-7) helicase complex at replication origins during G

193 replicative mini-chromosome-maintenance 2-7 (MCM2-7) helicase is loaded in Saccharomyces cerevisiae a

194 ant loss of the mini-chromosome maintenance (Mcm2-7) helicase proteins on chromatin.

195 ase minichromosome maintenance proteins 2-7 (MCM2-7) onto replication origins is a prerequisite for r

196 We focus on the minichromosome maintenance (MCM2-7) proteins, which form the core of the eukaryotic

197 5 (Cdc45) to minichromosome maintenance 2-7 (Mcm2-7).

198 al channel of Mcm2-7, Dpb11 dissociates from Mcm2-7, and Dpb11 binds to ssDNA, thereby allowing GINS

199 helicase in eukaryotes is composed of Cdc45, Mcm2-7, and GINS (CMG).

200 on fork helicase is comprised of CMG (Cdc45, Mcm2-7, and GINS) in eukaryotic cells, and the mechanism

201 MG replicative helicase (comprised of Cdc45, MCM2-7, and GINS), which obstructs the underlying cross-

202 helicase in eukaryotes is composed of Cdc45, Mcm2-7, and GINS.

203 Dpb11, although bound to Cdc45.Mcm2-7, can block the interaction between GINS and Mcm2-

204 trusion of ssDNA from the central channel of Mcm2-7, Dpb11 dissociates from Mcm2-7, and Dpb11 binds t

205 ve CMG [Cdc45 (cell division cycle gene 45), Mcm2-7, GINS (Go, Ichi, Ni, and San)] helicase.

206 The eukaryotic CMG (Cdc45, Mcm2-7, GINS) helicase consists of the Mcm2-7 hexameric

207 The eukaryotic replicative CMG (Cdc45, Mcm2-7, GINS) helicase contains a Mcm2-7 motor ring, wit

208 eukaryotic replicative helicase CMG (Cdc45, Mcm2-7, GINS) tightly binds Mcm10, an essential replicat

209 ed, the replicative DNA helicase CMG (CDC45, MCM2-7, GINS), which travels on the leading strand templ

210 the loading of the replicative DNA helicase, Mcm2-7, in inactive double hexameric form around DNA.

211 air/replication (Ku70-Ku80, DNA-PKcs, PARP1, MCM2-7, PCNA, RPA1) and RNA metabolism (RNA helicases, P

212 believed to be essential to recruit and load MCM2-7, the minichromosome maintenance protein complex,

213 t the core an AAA+ hetero-hexameric complex, Mcm2-7, together with GINS and Cdc45 form the active rep

214 cation defect with no recruitment of GINS to Mcm2-7, whereas expression of wild-type levels of sld3-m

215 e-activation factors the assembly of a Cdc45-MCM2-7-GINS (CMG) complex.

216 blished recruitment mechanisms whereby Cdc45-Mcm2-7-GINS (CMG) helicase binds Pol epsilon and tethers

217 Assembly of the Cdc45-Mcm2-7-GINS (CMG) replicative helicase complex must be r

218 ion are the assembly and activation of Cdc45-Mcm2-7-GINS (CMG) replicative helicase.

219 ring replication termination, the CMG (Cdc45-MCM2-7-GINS) helicase is polyubiquitylated by CRL2(Lrr1)

220 f an ORC-Cdc6-Mcm2-7 complex and an ORC-Cdc6-Mcm2-7-Mcm2-7 complex are reported, which together provi

221 2, which thereby leads to GINS attachment to Mcm2-7.

222 lication defect with no Cdc45 recruitment to Mcm2-7.

223 nd ssDNA inhibits the Dpb11 interaction with Mcm2-7.

224 sDNA, thereby allowing GINS to bind to Cdc45.Mcm2-7.

225 model in which Dpb11 first recruits Cdc45 to Mcm2-7.

226 the loading of the replicative DNA helicase, Mcm2-7.

227 , can block the interaction between GINS and Mcm2-7.

228 Dpb11 also competes with GINS for binding to Mcm2-7.

229 ished Go, Ichi, Ni, and San association with Mcm2-7.

230 e also found that Dpb11 can recruit Cdc45 to Mcm2-7.

231 hannel of Mcm2-7 triggers GINS attachment to Mcm2-7.

232 extrusion and subsequent GINS assembly with Mcm2-7.

233 ssembly, and the recruitment of pol alpha to Mcm2-7.

234 ing a mechanism for how GINS is recruited to Mcm2-7.

235 anism to recruit Dpb11 to DDK-phosphorylated Mcm2-7.

236 already inserted into the central channel of Mcm2-7.

237 trameric GINS (GG-Ichi-Nii-San) complex with Mcm2-7.

238 ichi-ni-san complex (GINS) to form the CDC45.MCM2-7.GINS (CMG) helicase complex.

239 ric changes through binding, forming a Cdc45/Mcm2-7/GINS (CMG) complex that is competent to unwind du

240 s but do not associate with the active CDC45/MCM2-7/GINS (CMG) replicative helicase.

241 5 form the active replicative helicase Cdc45/Mcm2-7/GINS (CMG).

242 a mitotic state, the replicative CMG (CDC45/MCM2-7/GINS) helicase undergoes ubiquitylation on its MC

243 n origin activation by regulating CMG (CDC45/MCM2-7/GINS) helicase.

244 -RC) assembly by loading a double hexamer of Mcm2-7: the core of the replicative helicase.

245 Our data suggests that MCM2 and 7 exert a role in ciliogenesis in post-mitotic

246 ays, which are mediated by ATR-CHK1 and WEE1-MCM2 and are responsible for regulating DNA replication

247 treatment, along with loss of expression of MCM2 and CDK1, and reduction in dNTP levels.

248 of cell cycle-associated proteins including MCM2 and cyclins A, E, D1/D3 in macrophages, without evi

249 dc7 phosphorylates the known Cdc7 substrates Mcm2 and histone H3 in vitro, and Cdc7 kinase activity i

250 ugh a unique DNA entry gate comprised of the Mcm2 and Mcm5 subunits.

251 The CMG has an active gate between subunits Mcm2 and Mcm5 that opens and closes in response to nucle

252 ubstantially weakens the interaction between Mcm2 and Mcm5, and Dbf4-Cdc7 phosphorylation of Mcm2 pro

253 anked by two pairs of gate-forming subunits, MCM2 and MCM5.

254 e binding site for Mcm10 on MCM includes the Mcm2 and Mcm6 subunits and overlaps that for the loading

255 DNA at a faster rate compared to 9 degrees N MCM2 and to Mth MCM.

256 cation, reduced levels of DDK-phosphorylated Mcm2, and diminished Go, Ichi, Ni, and San (GINS) associ

257 All MCM subunits contact DNA, from MCM2 at the 5'-end to MCM5 at the 3'-end of the DNA spir

258 ctive for stimulating DDK phosphorylation of Mcm2, binding to eighty-nucleotide ssDNA, and recruiting

259 in immunoprecipitation experiments show that MCM2 binds to transcription start sites of cilia inhibit

260 Additionally, structures of Mcm2 bound to an H3/H4 tetramer suggest a direct role of

261 that Sld3 stimulates DDK phosphorylation of Mcm2 by 11-fold.

262 timulates human DDK phosphorylation of human Mcm2 by 15-fold.

263 nt does not stimulate the phosphorylation of Mcm2 by Dbf4-dependent kinase (DDK) in vitro.

264 of CDC7 in addition to prolonged activity of MCM2 compared to drug-sensitive cells.

265 Inhibiting Dbf4-Cdc7 phosphorylation of Mcm2 confers a dominant-negative phenotype with a severe

266 DDK phosphorylation of human Mcm2 decreases the affinity of Mcm5 for Mcm2, suggesting

267 ent strand capture and release and show that MCM2 deficiency reduces DNA replication initiation in ge

268 ocations that are preferentially affected by MCM2 deficiency.

269 of recurrent focal CNVs in tumors arising in MCM2-deficient mice, consistent with a direct relationsh

270 Zebrafish depleted of MCM2 develop ciliopathy-phenotypes including microcephal

271 MCM (MCM7), which functions in complex with MCM2 during its canonical functions, reveals an overlapp

272 itment to Mcm2-7 with DDK phosphorylation of Mcm2 during S phase.

273 phosphorylates minichromosome maintenance 2 (Mcm2) during S phase in yeast, and Sld3 recruits cell di

274 memory, and in the absence of both Dpb3 and Mcm2 histone chaperone activity, nucleosomes did not rem

275 e growth defect conferred by DDK-phosphodead Mcm2 in budding yeast.

276 we show a hitherto unanticipated function of MCM2 in cilia formation in human cells and zebrafish tha

277 The Dbf4-Cdc7 kinase phosphorylates Mcm2 in vitro, but the in vivo role for Dbf4-Cdc7 phosph

278 that budding yeast Dbf4-Cdc7 phosphorylates Mcm2 in vivo under normal conditions during S phase.

279 n vivo role for Dbf4-Cdc7 phosphorylation of Mcm2 is unclear.

280 ver, mtp53 R273H expression enhanced overall MCM2 levels, promoted cell proliferation, and improved t

281 Thus, Dbf4-Cdc7 phosphorylation of Mcm2 may open the Mcm2-7 ring at the Mcm2-Mcm5 interface

282 positions the DNA right in front of the two Mcm2-Mcm5 gates, with each strand being pressed against

283 tion of Mcm2 may open the Mcm2-7 ring at the Mcm2-Mcm5 interface, allowing for single-stranded DNA ex

284 DNA entry gate, poised for insertion, at the Mcm2-Mcm5 interface.

285 tro, while in vivo analysis establishes that Mcm2/Mcm5 gate opening is essential for both helicase lo

286 ax), high MPP, and high blood flow expressed mcm2 (P = 0.036).

287 We also found that Mcm10 stimulates Mcm2 phosphorylation by DDK in vivo and in vitro.

288 mcm10-m2,3,4 are not explained by decreased Mcm2 phosphorylation by DDK, since the defects persist i

289 ls expressing sld3-m16 exhibit no detectable Mcm2 phosphorylation in vivo, reduced replication protei

290 We show here DDK-phosphoryled Mcm2 preferentially interacts with Cdc45 in vivo, and th

291 2 and Mcm5, and Dbf4-Cdc7 phosphorylation of Mcm2 promotes Mcm2-7 ring opening.

292 t the flexible N-terminal extension (NTE) of Mcm2 promotes the stable recruitment of Dbf4-dependent k

293 In non-cycling human fibroblasts, loss of MCM2 promotes transcription of a subset of genes, which

294 Meanwhile, DNA damage also activates WEE1-MCM2 signaling, which inhibits DNA replication initiatio

295 o, Dbf4-Cdc7 kinase (DDK) phosphorylation of Mcm2 substantially weakens the interaction between Mcm2

296 uman Mcm2 decreases the affinity of Mcm5 for Mcm2, suggesting a potential mechanism for helicase ring

297 plex-the DNA replicative helicase comprising MCM2 to MCM7(3,4)-that cause genomic instability render

298 Inhibiting Dbf4-Cdc7 phosphorylation of Mcm2 under wild-type expression conditions also results

299 ation-associated histone chaperones Dpb3 and Mcm2 were essential for nucleosome position memory, and

300 elting by stimulating DDK phosphorylation of Mcm2, which thereby leads to GINS attachment to Mcm2-7.