ライフサイエンスコーパス: MCM4

1 F345I), producing an apparently destabilized MCM4.

2 hat is specifically defective for binding to Mcm4.

3 5 with MCM3 and MCM2; and MCM6 with MCM2 and MCM4.

4 of the first 13 exons of the upstream gene, MCM4.

5 l domains (NTDs) of subunits Mcm2, Mcm6, and Mcm4.

6 rminal serine/threonine-rich domain (NSD) of Mcm4.

7 wing increased, premature phosphorylation of Mcm4.

8 ility, which was rescued by expression of WT MCM4.

9 trate that Dpb11 can directly recruit DDK to Mcm4.

10 orward genetic screen, is a viable allele of Mcm4.

11 osphorylated peptides from two MCM subunits (Mcm4, 6) and then recruits Cdc45.

12 only a specific subcomplex consisting of the MCM4, 6, and 7 subunits (MCM467) and not the MCM2-7 comp

13 idues in the Walker A and Walker B motifs of MCM4, -6, and -7 and determined that equivalent mutation

14 ical to those associated with the eukaryotic MCM4, -6, and -7 complex.

15 ase because a hexameric subcomplex formed by MCM4, -6, and -7 proteins has in vitro DNA helicase acti

16 Mcm4,6,7 and DnaB have different structural folds and ev

17 propose a "pump in ring" mechanism for both Mcm4,6,7 and DnaB, wherein a single-stranded DNA pump is

18 Mcm4,6,7 binds to only one strand of a duplex during unw

19 is shown that the Schizosaccharomyces pombe Mcm4,6,7 complex and archaeal minichromosome maintenance

20 Although the S. pombe Mcm4,6,7 complex required a 3'-overhang ssDNA region to

21 Mcm4,6,7 is a ring-shaped heterohexamer and the putative

22 The Mcm4,6,7 mechanism is very similar to DnaB, except the p

23 The Mcm4,6,7 ring also actively translocates along duplex DN

24 Mcm4,6,7 unwinding stops at a nick in either strand.

25 the proteins forming the catalytic helicase (MCM4,6,7) while the others have a loading or control fun

26 tative eukaryotic replication fork helicase, Mcm4,6,7, performs a similar activity.

27 In this study, we examine the mechanism of Mcm4,6,7.

28 and proliferation genes CCNA1, CCND2, IGFII, MCM4-6, PLK1, RPA2, and TYMS.

29 in the disassembly of the dimeric complex of Mcm4/6/7 and the loss of DNA helicase activity.

30 hese results support the hypothesis that the Mcm4/6/7 complex can function as a replication helicase.

31 These results suggest that the Mcm4/6/7 complex is a catalytic core of the Mcm complex

32 nteraction of either Mcm2 or Mcm3/5 with the Mcm4/6/7 complex resulted in the disassembly of the dime

33 showed that only the dimeric complex of the Mcm4/6/7 heterotrimer possessed single stranded DNA-depe

34 Mcm2/4/6/7 heterotetramer, the dimer of the Mcm4/6/7 heterotrimer, and the Mcm3/5 heterodimer.

35 ation of double heterohexameric complexes of Mcm4/6/7 on substrate DNA, which appeared to be essentia

36 the in vitro helicase activity of the mouse MCM4/6/7 subcomplex do not affect the in vivo function o

37 The double heterohexameric complex of Mcm4/6/7, in the presence of a single-strand DNA binding

38 D) of mini-chromosome maintenance subunit 4 (Mcm4), a subunit of the mini-chromosome maintenance (MCM

39 + (homologous to CDC45) and cdc21+ (encoding Mcm4, a component of the pre-replicative complex).

40 Mcm4, a helicase subunit, possesses an unstructured regu

41 Here, we demonstrate that Xenopus MCM4, a member of the MCM protein family related to Spcd

42 the level of two proliferation genes (ASPM, MCM4) after 2 weeks of therapy.

43 Whereas homozygosity for a disrupted Mcm4 allele (Mcm4(-)) caused preimplantation lethality,

44 e minichromosome maintenance complex protein Mcm4 alone and also of the Mcm2-7 complex and the dsDNA-

45 hich in turn promotes DDK phosphorylation of Mcm4 and -6 and subsequent origin activation.

46 ot Dbf4 severely inhibits phosphorylation of Mcm4 and DNA replication.

47 The MCM4 and DNA-PKcs promoters are in CpG islands separated

48 we believe to be the first human mutation in MCM4 and have shown that it is associated with adrenal i

49 whereas Cdc7 displayed association with both Mcm4 and Mcm5.

50 We identified DDK phosphorylation sites on Mcm4 and Mcm6 and found that phosphorylation of either s

51 Moreover, phosphomimicking mutants in Mcm4 and Mcm6 bind Sld3 without DDK and facilitate DDK-i

52 ve helicase at the N-terminal tails of Mcm2, Mcm4 and Mcm6.

53 ated markers including BMI1, cyclin E, ki67, MCM4 and MCM7 expression.

54 cantly associated with BMI1, cyclin E, Ki67, MCM4 and MCM7 expression.

55 We found that Mcm4 and Mcm7 form an active unwinding assembly.

56 associated with tumorigenesis through BMI1, MCM4 and MCM7.

57 immunostaining of CA9, BMI1, cyclin E, Ki67, MCM4 and MCM7.

58 cm complex is assembled on the chromatin the Mcm4 and the Mcm2 proteins are the only subunits phospho

59 ichromosome maintenance complex component 4 (MCM4), and RAD51 and up-regulation of p27(Kip1).

60 Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC a

61 nd down-regulation of cyclin B1, CDC2, CDK6, MCM4, and retinoblastoma.

62 A binding of a replicative helicase subunit, Mcm4, and the replication sliding clamp, PCNA, between d

63 nction as a heterohexamer, loading of Mcm2-, Mcm4-, and Mcm7-depleted complexes is likely to underlie

64 ation, we find that Mis5p (MCM6) and Cdc21p (MCM4) are tightly associated with one another in a core

65 As such we identify Mcm4 as the key ATPase in regulating pre-RC formation.

66 found that normal helicase loading triggers Mcm4 ATP-hydrolysis, which in turn leads to reorganisati

67 In cells where the checkpoint is activated, Mcm4 binds the Cds1 kinase and undergoes Cds1-dependent

68 A DDK phosphomimetic mutant of Mcm4 bound Dpb11 with substantially higher affinity than

69 Orc2 and Mcm4 bound near each of the replication initiation sites

70 ic evidence suggests that phosphorylation of Mcm4 by DDK is important for timely S phase progression

71 Because similar mutations in mcm2 and mcm4 cannot bypass DDK, Mcm5 protein may be a unique Mcm

72 as homozygosity for a disrupted Mcm4 allele (Mcm4(-)) caused preimplantation lethality, Mcm(Chaos3/-)

73 ed this method to the DNA replication factor mcm4/cdc21, and find that chromatin association occurs d

74 s bearing a GIN-causing hypomophic allele of Mcm4 (Chaos3), in conjunction with disruption alleles of

75 First, the Mcm4(Chaos3) allele, which disrupts MCM4:MCM6 interactio

76 asts derived from embryos homozygous for the Mcm4(Chaos3) allele.

77 While mcm4(Chaos3) causes replication stress in both haploid a

78 Mcm4(Chaos3) encodes a change in an evolutionarily invar

79 0 receptor was synthetically lethal with the Mcm4(Chaos3) helicase mutant.

80 ryos died late in gestation, indicating that Mcm4(Chaos3) is hypomorphic.

81 ved phenylalanine that aligns with the mouse Mcm4(Chaos3) mutation associated with chromosomal instab

82 The corresponding mouse allele, Mcm4(Chaos3), predisposes mice to mammary gland tumors.

83 DNA replication components, we utilized the Mcm4(Chaos3/Chaos3) ('Chaos3') mouse model that, by virt

84 Most notably, >80% of Mcm4(Chaos3/Chaos3) females succumbed to mammary adenoca

85 Cdc6 and Mcm4 chromatin association is aberrant in tom1Delta and

86 Thus, partial MCM4 deficiency results in a genetic syndrome of growth

87 Studies in vitro using purified DDK and Mcm4 demonstrate that hyperphosphorylation occurs at the

88 CD56(dim) phenotype was tightly dependent on MCM4-dependent cell division.

89 Interestingly, histological studies with Mcm4-depleted mice showed grossly abnormal adrenal morph

90 us81 promotes genomic instability and allows mcm4-dg cells to evade cell cycle arrest.

91 Furthermore, phosphorylation of MCM4 dramatically reduces its affinity for the chromatin

92 AP-1 was involved in the down-regulation of MCM4 expression.

93 Release of mcm4 from chromatin occurs during S phase and requires D

94 The arrangement of the PRKDC/MCM4 gene pair is similar to that of the ATM/E14(NPAT) g

95 human NK cell deficiency as mutation in the MCM4 gene, encoding minichromosome maintenance complex c

96 rigin at the upstream promoter region of the MCM4 gene.

97 ment or function is impaired and variants in MCM4, GINS1, MCM10, and GINS4 result in NKD.

98 Although Mcm4 has been identified as the critical DDK phosphoryla

99 rminal serine/threonine-rich domain (NSD) of Mcm4 has both inhibitory and facilitating roles in DNA r

100 establish that the eukaryote-specific NSD of Mcm4 has evolved to integrate several protein kinase reg

101 e conclude that Dpb11 functions with DDK and Mcm4 in a positive amplification mechanism to trigger th

102 This gene is most similar to MCM4 in eukaryotic cells.

103 cyclinB protein kinase, which phosphorylates MCM4 in vitro at identical sites as the ones phosphoryla

104 The immobile fraction of MCM2 and MCM4 increases during G1 phase, suggestive of reiterativ

105 by Sld3, Dbf4, and the regulatory domain of Mcm4 intersect to control origin firing and replication

106 the cell cycle-dependent phosphorylation of MCM4 is a mechanism which inactivates the MCM complex fr

107 MCM4 is an essential component of a protein complex that

108 In this complex, Mcm4 is hyperphosphorylated.

109 on is specific for cdc2 protein kinase since MCM4 is not a substrate for other members of the cdk fam

110 Since MCM4 is one part of a MCM2-7 complex recently confirmed

111 cipitated throughout the cell cycle, whereas MCM4 is reduced in the complex in late S and G(2), reapp

112 Upon overexpressing cdc18, we show that mcm4 is required for re-replication of the genome in the

113 We show that, in telophase, MCM2 and MCM4 maintain transient interactions with chromatin, exh

114 P118 is conserved between Mcm3, Mcm4, Mcm5, and Mcm7.

115 optotic genes (e.g., MYC, MYBL2, BUB1, MCM2, MCM4, MCM5, and survivin) and up-regulation of several p

116 nd MCM7, and MCM8 co-immunoprecipitates with MCM4, MCM6 and MCM7, proteins reportedly forming a helic

117 verted sideways by OB hairpin-loops of Mcm3, Mcm4, Mcm6, and Mcm7.

118 With the exception of Mcm4, Mcm6, and Psf1, knockdown of individual CMG genes

119 We studied the mechanism of the Mcm4-Mcm6-Mcm7 complex, a useful model system because th

120 The Mcm4/Mcm7 and Mcm4/Mcm6/Mcm7 assemblies can open to load onto circular

121 4/Mcm7 results in the formation of an active Mcm4/Mcm6/Mcm7 helicase assembly.

122 by a steric exclusion mechanism, similar to Mcm4/Mcm6/Mcm7.

123 rst, the Mcm4(Chaos3) allele, which disrupts MCM4:MCM6 interaction, triggers a Dicer1 and Drosha-depe

124 ntly lower levels of the replication factors Mcm4, Mcm7, and Cdc45 at replication origins in met30 mu

125 ific defect in loading of initiator proteins Mcm4, Mcm7, and to a lesser degree, Mcm2 onto chromatin

126 The Mcm4-Mcm7 complex forms a ringed-shaped hexamer that unw

127 The Mcm4-Mcm7 complex has a high level of ATPase activity th

128 The Mcm4/Mcm7 and Mcm4/Mcm6/Mcm7 assemblies can open to load

129 The addition of Mcm6 to Mcm4/Mcm7 results in the formation of an active Mcm4/Mcm

130 Mcm4 (minichromosome maintenance-deficient 4 homolog) en

131 ified mutations in a conserved and essential Mcm4 motif that permit loading of two Mcm2-7 complexes b

132 aded Mcm2-7 harboring the DDK phosphomimetic Mcm4 mutant bound GINS in the presence of Dpb11, suggest

133 ing this docking domain (Mcm2DeltaDDD) or an Mcm4 mutant lacking a previously identified DDK docking

134 By combining an mcm4 mutant lacking the inhibitory activity with mutatio

135 PCNA and MCM4 mutants had similar phenotypes to Orc mutants.

136 t was observed that rem1.2, orc1a, ppd1, and mcm4 mutants showed different degrees of reduction in ro

137 sponse is different in temperature-sensitive mcm4 mutants, affecting a subunit of the MCM replicative

138 iously published reports for Orc2, Orc5, and Mcm4 mutants.

139 e ubiquitous but heterogeneous impact of the MCM4 mutation in various tissues.

140 A similar mcm4 mutation is synthetically lethal with the mcm5 muta

141 rate that hyperphosphorylation occurs at the Mcm4 N terminus.

142 DK phosphorylation at the distal part of the Mcm4 NSD becomes crucial.

143 utations within two separate segments of the Mcm4 NSD.

144 r displaces the NSD from its binding site on Mcm4-NTD, facilitating an immediate targeting of this mo

145 ble-hexamer interface and phosphorylation of Mcm4 on the opposite hexamer.

146 sitivity was found to be specific to Mcm2 or Mcm4 overexpression, further pointing to the importance

147 These results suggest that the changes in Mcm4 phosphorylation regulate pre-Rc assembly and the fu

148 MCM4 phosphorylation starts concomitantly with the clear

149 and DNA replication, substantially decreased Mcm4 phosphorylation, and decreased association of GINS

150 cts with PP1 and that PP1 prevents premature Mcm4 phosphorylation.

151 ynthetic lethality, suggesting that Mcm2 and Mcm4 play overlapping roles in the association of DDK wi

152 The regulatory domain of Mcm4 plays an important role in the timing of late origi

153 Both promoters lack TATA boxes, and the MCM4 promoter also lacks an initiator (Inr) element but

154 orylation of the mitotic hyperphosphorylated Mcm4 protein.

155 gen (PCNA) and minichromosome maintenance 4 (MCM4) proteins without changing the amount of pcna and m

156 tions the effect of mutations that alter the Mcm4 regulatory domain and the Rad53 targets, Sld3 and D

157 This effect is parallel to the role of the Mcm4 regulatory domain in monitoring fork progression.

158 omorph mutations in sld3 are suppressed by a mcm4 regulatory domain mutation.

159 The mitotic phosphorylation of Mcm4 requires Cdc2-cyclin B and other unknown kinases.

160 under genotoxic stress when the controls on Mcm4, Sld3, and Dbf4 are simultaneously eliminated.

161 ex contains an intermediately phosphorylated Mcm4 subunit and is produced by partial dephosphorylatio

162 Complete dephosphorylation of the Mcm4 subunit inactivates the Mcm complex and prevents it

163 During mitosis, the Mcm4 subunit is hyperphosphorylated, while the other sub

164 Following exit from mitosis, the Mcm4 subunit of the cytosolic interphase complex undergo

165 cells, inhibiting the origin binding of the Mcm4 subunit of the MCM licensing factor.

166 strate affinity and bind specifically to the MCM4 subunit.

167 substantially higher affinity than wild-type Mcm4, suggesting a mechanism to recruit Dpb11 to DDK-pho

168 at, by virtue of an amino-acid alteration in MCM4 that destabilizes the MCM2-7 DNA replicative helica

169 ) in minichromosome maintenance-deficient 4 (MCM4) that was predicted to result in a severely truncat

170 Binding of mcm4 to chromatin requires orc1 and cdc18 (homologous to

171 eins without changing the amount of pcna and mcm4 transcripts.

172 MCM4 undergoes cell cycle-dependent phosphorylation both

173 nance and repair, proteins, namely, MCM2 and MCM4, were highly expressed in the 16E6/FN123 compared t

174 expression of minichromosome maintenance 4 (MCM4), which leads to a decreased loading of the MCM com

175 ing, we identified the disease-causing gene, MCM4, which encodes a component of the MCM2-7 helicase c