Genomes and Genes
Gene Symbol: MCM4
Description: MCM DNA helicase complex subunit MCM4
Alias: CDC54, HCD21, MCM DNA helicase complex subunit MCM4
Species: Saccharomyces cerevisiae S288c
- Morohashi H, Maculins T, Labib K. The amino-terminal TPR domain of Dia2 tethers SCF(Dia2) to the replisome progression complex. Curr Biol. 2009;19:1943-9 pubmed publisher..Our findings suggest that the amino-terminal domains of other F box proteins might also play an analogous regulatory role, controlling the localization of the cognate SCF complexes. ..
- Kawasaki Y, Kim H, Kojima A, Seki T, Sugino A. Reconstitution of Saccharomyces cerevisiae prereplicative complex assembly in vitro. Genes Cells. 2006;11:745-56 pubmed
- Calzada A, Hodgson B, Kanemaki M, Bueno A, Labib K. Molecular anatomy and regulation of a stable replisome at a paused eukaryotic DNA replication fork. Genes Dev. 2005;19:1905-19 pubmed..We also show that paused forks at analogous barriers in the rDNA are regulated similarly. These data indicate that paused and stalled eukaryotic replisomes resemble each other but are regulated differently. ..
- Bochman M, Bell S, Schwacha A. Subunit organization of Mcm2-7 and the unequal role of active sites in ATP hydrolysis and viability. Mol Cell Biol. 2008;28:5865-73 pubmed publisher..Our conclusions predict a structural discontinuity between Mcm2 and Mcm5 and demonstrate that in contrast to other hexameric helicases, the six Mcm2-7 active sites are functionally distinct. ..
- Mimura S, Komata M, Kishi T, Shirahige K, Kamura T. SCF(Dia2) regulates DNA replication forks during S-phase in budding yeast. EMBO J. 2009;28:3693-705 pubmed publisher..These results demonstrate that Dia2 is involved in the regulation of replisome activity through a direct interaction with replisome components. ..
- Bochman M, Schwacha A. The Mcm2-7 complex has in vitro helicase activity. Mol Cell. 2008;31:287-93 pubmed publisher..Our results show that purified Mcm2-7 acts as a helicase, provides functional evidence of a Mcm2/5 gate, and lays the foundation for future mechanistic studies of this critical factor. ..
- Remus D, Beuron F, Tolun G, Griffith J, Morris E, Diffley J. Concerted loading of Mcm2-7 double hexamers around DNA during DNA replication origin licensing. Cell. 2009;139:719-30 pubmed publisher..Our work has significant implications for understanding how eukaryotic DNA replication origins are chosen and licensed, how replisomes assemble during initiation, and how unwinding occurs during DNA replication. ..
- Evrin C, Clarke P, Zech J, Lurz R, Sun J, Uhle S, et al. A double-hexameric MCM2-7 complex is loaded onto origin DNA during licensing of eukaryotic DNA replication. Proc Natl Acad Sci U S A. 2009;106:20240-5 pubmed publisher..Our results provide key insights into mechanisms of pre-RC formation and have important implications for understanding the role of the MCM2-7 in establishment of bidirectional replication forks. ..
- Bochman M, Schwacha A. Differences in the single-stranded DNA binding activities of MCM2-7 and MCM467: MCM2 and MCM5 define a slow ATP-dependent step. J Biol Chem. 2007;282:33795-804 pubmed..Although all six subunits function at the replication fork, only a specific subcomplex consisting of the MCM4, 6, and 7 subunits (MCM467) and not the MCM2-7 complex exhibits DNA helicase activity in vitro...
- Devault A, Gueydon E, Schwob E. Interplay between S-cyclin-dependent kinase and Dbf4-dependent kinase in controlling DNA replication through phosphorylation of yeast Mcm4 N-terminal domain. Mol Biol Cell. 2008;19:2267-77 pubmed publisher..Here, we show that budding yeast Mcm4 is phosphorylated in vivo during S phase in a manner dependent on the presence of five CDK phosphoacceptor residues ..
- Kanter D, Bruck I, Kaplan D. Mcm subunits can assemble into two different active unwinding complexes. J Biol Chem. 2008;283:31172-82 pubmed publisher..We studied the mechanism of the Mcm4-Mcm6-Mcm7 complex, a useful model system because this complex has helicase activity in vitro...
- Sheu Y, Stillman B. The Dbf4-Cdc7 kinase promotes S phase by alleviating an inhibitory activity in Mcm4. Nature. 2010;463:113-7 pubmed publisher..Here we show that the amino terminal serine/threonine-rich domain (NSD) of Mcm4 has both inhibitory and facilitating roles in DNA replication control and that the sole essential function of DDK ..
- Sheu Y, Stillman B. Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression. Mol Cell. 2006;24:101-13 pubmed..In this complex, Mcm4 is hyperphosphorylated...
- Randell J, Fan A, Chan C, Francis L, Heller R, Galani K, et al. Mec1 is one of multiple kinases that prime the Mcm2-7 helicase for phosphorylation by Cdc7. Mol Cell. 2010;40:353-63 pubmed publisher..We identified DDK phosphorylation sites on Mcm4 and Mcm6 and found that phosphorylation of either subunit suffices for cell proliferation...
- Davey M, Indiani C, O Donnell M. Reconstitution of the Mcm2-7p heterohexamer, subunit arrangement, and ATP site architecture. J Biol Chem. 2003;278:4491-9 pubmed..The data predict which subunits in the ATPase pairs bind the ATP that is hydrolyzed and indicate the arrangement of subunits in the Mcm2-7p heterohexamer. ..
- Bruck I, Kaplan D. Dbf4-Cdc7 phosphorylation of Mcm2 is required for cell growth. J Biol Chem. 2009;284:28823-31 pubmed publisher..We conclude that DDK phosphorylation of Mcm2 is required for cell growth. ..
- Ramer M, Suman E, Richter H, Stanger K, Spranger M, Bieberstein N, et al. Dbf4 and Cdc7 proteins promote DNA replication through interactions with distinct Mcm2-7 protein subunits. J Biol Chem. 2013;288:14926-35 pubmed publisherThe essential cell cycle target of the Dbf4/Cdc7 kinase (DDK) is the Mcm2-7 helicase complex. Although Mcm4 has been identified as the critical DDK phosphorylation target for DNA replication, it is not well understood which of the six ..
- Holzen T, Sclafani R. Genetic interaction of RAD53 protein kinase with histones is important for DNA replication. Cell Cycle. 2010;9:4735-47 pubmed..We propose a model in which Rad53 acts as a "nucleosome buffer," interacting with origins of replication to prevent the binding of excess histones to origin DNA and to maintain proper chromatin configuration. ..
- Lam S, Ma X, Sing T, Shilton B, Brandl C, Davey M. The PS1 hairpin of Mcm3 is essential for viability and for DNA unwinding in vitro. PLoS ONE. 2013;8:e82177 pubmed publisher..Together, these findings indicate that the PS1 hairpins in the Mcm2-7 subunits have important and distinct functions, most evident by the essential nature of the Mcm3 PS1 hairpin in DNA unwinding. ..
- Froelich C, Kang S, Epling L, Bell S, Enemark E. A conserved MCM single-stranded DNA binding element is essential for replication initiation. elife. 2014;3:e01993 pubmed publisher..Our findings identify an important MCM-ssDNA interaction and suggest it functions during helicase activation to select the strand for translocation. DOI: http://dx.doi.org/10.7554/eLife.01993.001...
- Pérez Arnaiz P, Bruck I, Colbert M, Kaplan D. An intact Mcm10 coiled-coil interaction surface is important for origin melting, helicase assembly and the recruitment of Pol-? to Mcm2-7. Nucleic Acids Res. 2017;45:7261-7275 pubmed publisher..We also detected diminished GINS and pol-? recruitment to the Mcm2-7 complex. We conclude that an intact Mcm10 coiled-coil interaction surface is important for origin melting, helicase assembly, and the recruitment of pol ? to Mcm2-7. ..
- Loo S, Fox C, Rine J, Kobayashi R, Stillman B, Bell S. The origin recognition complex in silencing, cell cycle progression, and DNA replication. Mol Biol Cell. 1995;6:741-56 pubmed..The silencing defect caused by orc5-1 strengthened previous connections between ORC and silencing, and combined with the phenotypes caused by orc2 mutations, suggested that the complex itself functions in both processes. ..
- Merchant A, Kawasaki Y, Chen Y, Lei M, Tye B. A lesion in the DNA replication initiation factor Mcm10 induces pausing of elongation forks through chromosomal replication origins in Saccharomyces cerevisiae. Mol Cell Biol. 1997;17:3261-71 pubmed..This novel phenotype suggests a unique role for the Mcm10 protein in the initiation of DNA synthesis at replication origins. ..
- Sheu Y, Kinney J, Stillman B. Concerted activities of Mcm4, Sld3, and Dbf4 in control of origin activation and DNA replication fork progression. Genome Res. 2016;26:315-30 pubmed publisher..b>Mcm4, a helicase subunit, possesses an unstructured regulatory domain that mediates control from multiple kinase ..
- Villa F, Simon A, Ortiz Bazan M, Kilkenny M, Wirthensohn D, Wightman M, et al. Ctf4 Is a Hub in the Eukaryotic Replisome that Links Multiple CIP-Box Proteins to the CMG Helicase. Mol Cell. 2016;63:385-96 pubmed publisher..Most strikingly, Ctf4-dependent recruitment of CIP-box proteins couples other processes to DNA synthesis, including rDNA copy-number regulation. ..
- Kubota T, Hiraga S, Yamada K, Lamond A, Donaldson A. Quantitative proteomic analysis of chromatin reveals that Ctf18 acts in the DNA replication checkpoint. Mol Cell Proteomics. 2011;10:M110.005561 pubmed publisher..Identification of Ctf18 as a checkpoint protein highlights the usefulness of chromatin proteomic analysis for understanding the in vivo function of proteins that mediate chromatin transactions. ..
- Sun J, Shi Y, Georgescu R, Yuan Z, Chait B, Li H, et al. The architecture of a eukaryotic replisome. Nat Struct Mol Biol. 2015;22:976-82 pubmed publisher..Our work reveals an unexpected configuration of the eukaryotic replisome, suggests possible reasons for this architecture and provides a basis for further structural and biochemical replisome studies. ..
- Han J, Li Q, McCullough L, Kettelkamp C, Formosa T, Zhang Z. Ubiquitylation of FACT by the cullin-E3 ligase Rtt101 connects FACT to DNA replication. Genes Dev. 2010;24:1485-90 pubmed publisher..Origin function is compromised in cells lacking Rtt101 or with an Spt16 mutation. These findings identify Spt16 as an Rtt101 substrate, and suggest that Spt16 ubiquitylation is important for FACT to function during DNA replication. ..
- Bruck I, Kaplan D. Origin single-stranded DNA releases Sld3 protein from the Mcm2-7 complex, allowing the GINS tetramer to bind the Mcm2-7 complex. J Biol Chem. 2011;286:18602-13 pubmed publisher..We also show that origin single-stranded DNA promotes the formation of the CMG complex. We conclude that origin single-stranded DNA releases Sld3 from Mcm2-7, allowing GINS to bind Mcm2-7. ..
- Labib K, Diffley J, Kearsey S. G1-phase and B-type cyclins exclude the DNA-replication factor Mcm4 from the nucleus. Nat Cell Biol. 1999;1:415-22 pubmed..We show here that, in budding yeast, CDKs exclude the essential prereplicative-complex component Mcm4 from the nucleus...
- Evrin C, Fernández Cid A, Riera A, Zech J, Clarke P, Herrera M, et al. The ORC/Cdc6/MCM2-7 complex facilitates MCM2-7 dimerization during prereplicative complex formation. Nucleic Acids Res. 2014;42:2257-69 pubmed publisher..Our work identifies the OCM complex as competent for MCM2-7 dimerization, reveals MCM2-7 dimerization as a limiting step during pre-RC formation and defines critical mechanisms that explain how origins are licensed. ..
- Biswas Fiss E, Khopde S, Biswas S. The Mcm467 complex of Saccharomyces cerevisiae is preferentially activated by autonomously replicating DNA sequences. Biochemistry. 2005;44:2916-25 pubmed..Our results also indicate that the yeast replication protein A stimulated the ATPase activity of the Mcm467 complex. ..
- Li X, Schimenti J, Tye B. Aneuploidy and improved growth are coincident but not causal in a yeast cancer model. PLoS Biol. 2009;7:e1000161 pubmed publisher..of a link between aneuploidy and mutations allowing improved growth, using Saccharomyces cerevisiae containing a mcm4 helicase allele that was shown to cause cancer in mice...
- Maculins T, Nkosi P, Nishikawa H, Labib K. Tethering of SCF(Dia2) to the Replisome Promotes Efficient Ubiquitylation and Disassembly of the CMG Helicase. Curr Biol. 2015;25:2254-9 pubmed publisher..Residual ubiquitylation of Mcm7 in dia2-Î”TPR cells is still CMG specific, highlighting the complex regulation of the final stages of chromosome replication, about which much still remains to be learned. ..
- Ramey C, Sclafani R. Functional conservation of the pre-sensor one beta-finger hairpin (PS1-hp) structures in mini-chromosome maintenance proteins of Saccharomyces cerevisiae and archaea. G3 (Bethesda). 2014;4:1319-26 pubmed publisher..Mutation of the Mcm4p PS1-hp beta-finger (mcm4-HA K658A::TRP1) does not have a growth defect, indicating different functional contributions of the PS1-hp beta-..
- Hennessy K, Lee A, Chen E, Botstein D. A group of interacting yeast DNA replication genes. Genes Dev. 1991;5:958-69 pubmed..and CDC47 were originally isolated as suppressors of mutations in two other cell-division-cycle genes (CDC45 and CDC54)...
- Langston L, Mayle R, Schauer G, Yurieva O, Zhang D, Yao N, et al. Mcm10 promotes rapid isomerization of CMG-DNA for replisome bypass of lagging strand DNA blocks. elife. 2017;6: pubmed publisher..We demonstrate that bypass occurs without displacement of the blocks and therefore Mcm10 must isomerize the CMG-DNA complex to achieve the bypass function. ..
- Liku M, Nguyen V, Rosales A, Irie K, Li J. CDK phosphorylation of a novel NLS-NES module distributed between two subunits of the Mcm2-7 complex prevents chromosomal rereplication. Mol Biol Cell. 2005;16:5026-39 pubmed
- Li X, Tye B. Ploidy dictates repair pathway choice under DNA replication stress. Genetics. 2011;187:1031-40 pubmed publisher..The corresponding mouse allele, Mcm4(Chaos3), predisposes mice to mammary gland tumors...
- Sengupta S, van Deursen F, De Piccoli G, Labib K. Dpb2 integrates the leading-strand DNA polymerase into the eukaryotic replisome. Curr Biol. 2013;23:543-52 pubmed publisher..Second, it plays an equally important role after initiation, because it links the leading strand DNA polymerase to the Cdc45-MCM-GINS helicase within the replisome. ..
- Wu R, Wang J, Liang C. Cdt1p, through its interaction with Mcm6p, is required for the formation, nuclear accumulation and chromatin loading of the MCM complex. J Cell Sci. 2012;125:209-19 pubmed publisher..Our findings suggest a function for Cdt1p in promoting the assembly of the MCM complex and maintaining its integrity by interacting with Mcm6p. ..
- Deegan T, Yeeles J, Diffley J. Phosphopeptide binding by Sld3 links Dbf4-dependent kinase to MCM replicative helicase activation. EMBO J. 2016;35:961-73 pubmed publisher..Sld3 binds specifically to DDK-phosphorylated peptides from two MCM subunits (Mcm4, 6) and then recruits Cdc45...
- Yuan Z, Riera A, Bai L, Sun J, Nandi S, Spanos C, et al. Structural basis of Mcm2-7 replicative helicase loading by ORC-Cdc6 and Cdt1. Nat Struct Mol Biol. 2017;24:316-324 pubmed publisher..Flexible Mcm2-7 winged-helix domains (WHDs) engage ORC-Cdc6. A three-domain Cdt1 configuration embraces Mcm2, Mcm4, and Mcm6, thus comprising nearly half of the hexamer...
- Douglas M, Diffley J. Recruitment of Mcm10 to Sites of Replication Initiation Requires Direct Binding to the Minichromosome Maintenance (MCM) Complex. J Biol Chem. 2016;291:5879-88 pubmed publisher..These findings indicate that Mcm10 is localized to replication initiation sites by directly binding MCM through the Mcm10 C terminus. ..
- Quan Y, Xia Y, Liu L, Cui J, Li Z, Cao Q, et al. Cell-Cycle-Regulated Interaction between Mcm10 and Double Hexameric Mcm2-7 Is Required for Helicase Splitting and Activation during S Phase. Cell Rep. 2015;13:2576-2586 pubmed publisher..Therefore, we propose an essential role for Mcm10 in Mcm2-7 remodeling through formation of a cell-cycle-regulated supercomplex with DHs. ..
- Ma X, Stead B, Rezvanpour A, Davey M. The effects of oligomerization on Saccharomyces cerevisiae Mcm4/6/7 function. BMC Biochem. 2010;11:37 pubmed publisher..Mcm) 2, 3, 4, 5, 6 and 7 are related by sequence and form a variety of complexes that unwind DNA, including Mcm4/6/7...
- Su N, Flick K, Kaiser P. The F-box protein Met30 is required for multiple steps in the budding yeast cell cycle. Mol Cell Biol. 2005;25:3875-85 pubmed..defects, chromatin immunoprecipitation experiments revealed significantly lower levels of the replication factors Mcm4, Mcm7, and Cdc45 at replication origins in met30 mutants than in wild-type cells...
- Wilmes G, Bell S. The B2 element of the Saccharomyces cerevisiae ARS1 origin of replication requires specific sequences to facilitate pre-RC formation. Proc Natl Acad Sci U S A. 2002;99:101-6 pubmed..The function of these mutant sequences is rescued by Cdc6p overexpression. We propose that the B2 element requires specific sequences to bind a component of the pre-RC. ..
- Watase G, Takisawa H, Kanemaki M. Mcm10 plays a role in functioning of the eukaryotic replicative DNA helicase, Cdc45-Mcm-GINS. Curr Biol. 2012;22:343-9 pubmed publisher..Thus, Mcm10 plays an essential role in functioning of the CMG replicative helicase independent of assembly of a stable CMG complex at origins. ..
- Bruck I, Kaplan D. GINS and Sld3 compete with one another for Mcm2-7 and Cdc45 binding. J Biol Chem. 2011;286:14157-67 pubmed publisher..Our results are consistent with a model wherein GINS trades places with Sld3 at a replication origin, contributing to the activation of the replication fork helicase. ..
- Sheu Y, Kinney J, Lengronne A, Pasero P, Stillman B. Domain within the helicase subunit Mcm4 integrates multiple kinase signals to control DNA replication initiation and fork progression. Proc Natl Acad Sci U S A. 2014;111:E1899-908 pubmed publisher..the structurally disordered N-terminal serine/threonine-rich domain (NSD) of mini-chromosome maintenance subunit 4 (Mcm4), a subunit of the mini-chromosome maintenance (MCM) replicative helicase complex...
- Sun J, Fernández Cid A, Riera A, Tognetti S, Yuan Z, Stillman B, et al. Structural and mechanistic insights into Mcm2-7 double-hexamer assembly and function. Genes Dev. 2014;28:2291-303 pubmed publisher..The data suggest how the double hexamer is assembled and how helicase activity is regulated during DNA licensing, with implications for cell cycle control of DNA replication and genome stability. ..
- Leon R, Tecklenburg M, Sclafani R. Functional conservation of beta-hairpin DNA binding domains in the Mcm protein of Methanobacterium thermoautotrophicum and the Mcm5 protein of Saccharomyces cerevisiae. Genetics. 2008;179:1757-68 pubmed publisher..A similar mcm4 mutation is synthetically lethal with the mcm5 mutation...
- Huo L, Wu R, Yu Z, Zhai Y, Yang X, Chan T, et al. The Rix1 (Ipi1p-2p-3p) complex is a critical determinant of DNA replication licensing independent of their roles in ribosome biogenesis. Cell Cycle. 2012;11:1325-39 pubmed publisher..These results establish a new framework for the hierarchy of pre-RC proteins, where the Ipi1p-2p-3p complex provides a critical link between ORC-Noc3p and Cdc6p-Cdt1p-MCM in replication licensing. ..
- Yaakov G, Duch A, Garcia Rubio M, Clotet J, Jimenez J, Aguilera A, et al. The stress-activated protein kinase Hog1 mediates S phase delay in response to osmostress. Mol Biol Cell. 2009;20:3572-82 pubmed publisher..The two mechanisms of Hog1 action lead to delayed firing of origins and prolonged replication, respectively. The Hog1-dependent delay of replication could be important to allow Hog1 to induce gene expression before replication. ..
- GarcÃa RodrÃguez L, De Piccoli G, Marchesi V, Jones R, Edmondson R, Labib K. A conserved PolÏµ binding module in Ctf18-RFC is required for S-phase checkpoint activation downstream of Mec1. Nucleic Acids Res. 2015;43:8830-8 pubmed publisher..These findings indicate that the association of Ctf18-RFC with Pol Ïµ at defective replication forks is a key step in activation of the S-phase checkpoint. ..
- Maric M, Maculins T, De Piccoli G, Labib K. Cdc48 and a ubiquitin ligase drive disassembly of the CMG helicase at the end of DNA replication. Science. 2014;346:1253596 pubmed publisher..These findings indicate that the end of chromosome replication in eukaryotes is controlled in a similarly complex fashion to the much-better-characterized initiation step. ..
- Langston L, Zhang D, Yurieva O, Georgescu R, Finkelstein J, Yao N, et al. CMG helicase and DNA polymerase Îµ form a functional 15-subunit holoenzyme for eukaryotic leading-strand DNA replication. Proc Natl Acad Sci U S A. 2014;111:15390-5 pubmed publisher..Direct binding between Pol Îµ and CMG provides an explanation for specific targeting of Pol Îµ to the leading strand and provides clear mechanistic evidence for how strand asymmetry is maintained in eukaryotes. ..
- Labib K, Kearsey S, Diffley J. MCM2-7 proteins are essential components of prereplicative complexes that accumulate cooperatively in the nucleus during G1-phase and are required to establish, but not maintain, the S-phase checkpoint. Mol Biol Cell. 2001;12:3658-67 pubmed..of MCM2-7 proteins, since degradation of Mcm2, 3, 6, or 7 during G1-phase, after pre-RC formation, causes loss of Mcm4 from the nucleus...
- Bruck I, Kanter D, Kaplan D. Enabling association of the GINS protein tetramer with the mini chromosome maintenance (Mcm)2-7 protein complex by phosphorylated Sld2 protein and single-stranded origin DNA. J Biol Chem. 2011;286:36414-26 pubmed publisher..Furthermore, origin ssDNA may stimulate the formation of the CMG complex by alleviating inhibitory interactions between Sld2 with Mcm2-7. ..
- Bruck I, Kaplan D. The replication initiation protein Sld2 regulates helicase assembly. J Biol Chem. 2014;289:1948-59 pubmed publisher..We also study a mutant of Sld2 that is defective in binding DNA, sld2-DNA, and find that sld2-DNA cells exhibit no GINS-Mcm2-7 interaction. These data suggest that Sld2 association with DNA is required for CMG assembly in S phase...