ライフサイエンスコーパス: MCM4

1 5 with MCM3 and MCM2; and MCM6 with MCM2 and MCM4.

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

3 trate that Dpb11 can directly recruit DDK to Mcm4.

4 wing increased, premature phosphorylation of Mcm4.

5 hat is specifically defective for binding to Mcm4.

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

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

8 F345I), producing an apparently destabilized MCM4.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

38 Mcm4, a helicase subunit, possesses an unstructured regu

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

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

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

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

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

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

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

46 whereas Cdc7 displayed association with both Mcm4 and Mcm5.

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

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

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

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

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

52 associated with tumorigenesis through BMI1, MCM4 and MCM7.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

77 Cdc6 and Mcm4 chromatin association is aberrant in tom1Delta and

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

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

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

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

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

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

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

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

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

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

88 Although Mcm4 has been identified as the critical DDK phosphoryla

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

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

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

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

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

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

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

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

97 MCM4 is an essential component of a protein complex that

98 In this complex, Mcm4 is hyperphosphorylated.

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

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

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

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

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

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

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

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

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

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

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

110 4/Mcm7 results in the formation of an active Mcm4/Mcm6/Mcm7 helicase assembly.

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

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

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

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

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

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

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

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

119 Mcm4 (minichromosome maintenance-deficient 4 homolog) en

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

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

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

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

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

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

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

127 rate that hyperphosphorylation occurs at the Mcm4 N terminus.

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

129 utations within two separate segments of the Mcm4 NSD.

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

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

132 MCM4 phosphorylation starts concomitantly with the clear

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

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

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

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

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

138 orylation of the mitotic hyperphosphorylated Mcm4 protein.

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

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

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

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

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

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

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

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

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

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

149 strate affinity and bind specifically to the MCM4 subunit.

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

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

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

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

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

155 MCM4 undergoes cell cycle-dependent phosphorylation both

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

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