MCM6

Summary

Gene Symbol: MCM6
Description: MCM DNA helicase complex subunit MCM6
Alias: MCM DNA helicase complex subunit MCM6
Species: Saccharomyces cerevisiae S288c

Top Publications

  1. 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...
  2. 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. ..
  3. 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...
  4. Sun J, Evrin C, Samel S, Fernández Cid A, Riera A, Kawakami H, et al. Cryo-EM structure of a helicase loading intermediate containing ORC-Cdc6-Cdt1-MCM2-7 bound to DNA. Nat Struct Mol Biol. 2013;20:944-51 pubmed publisher
    ..The resulting ORC-Cdc6 helicase loader shows a notable structural similarity to the replication factor C clamp loader, suggesting a conserved mechanism of action. ..
  5. 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
    ..We propose that the DNA binding differences between MCM2-7 and MCM467 correspond to a conformational change at the MCM2/5 active site with putative regulatory significance. ..
  6. 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
    ..Our data indicate that pre-RCs do not play a direct role in checkpoint control during chromosome replication. ..
  7. 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. ..
  8. Kaplan D, Davey M, O Donnell M. Mcm4,6,7 uses a "pump in ring" mechanism to unwind DNA by steric exclusion and actively translocate along a duplex. J Biol Chem. 2003;278:49171-82 pubmed
  9. Takara T, Bell S. Multiple Cdt1 molecules act at each origin to load replication-competent Mcm2-7 helicases. EMBO J. 2011;30:4885-96 pubmed publisher

More Information

Publications63

  1. Coster G, Frigola J, Beuron F, Morris E, Diffley J. Origin licensing requires ATP binding and hydrolysis by the MCM replicative helicase. Mol Cell. 2014;55:666-77 pubmed publisher
    ..This work alters our view of how ATP is used by licensing factors to assemble pre-RCs. ..
  2. Francis L, Randell J, Takara T, Uchima L, Bell S. Incorporation into the prereplicative complex activates the Mcm2-7 helicase for Cdc7-Dbf4 phosphorylation. Genes Dev. 2009;23:643-54 pubmed publisher
  3. 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. ..
  4. Labib K, Tercero J, Diffley J. Uninterrupted MCM2-7 function required for DNA replication fork progression. Science. 2000;288:1643-7 pubmed
    ..Restricting MCM loading to the G(1) phase ensures that initiation and elongation occur just once per cell cycle. ..
  5. Jee J, Mizuno T, Kamada K, Tochio H, Chiba Y, Yanagi K, et al. Structure and mutagenesis studies of the C-terminal region of licensing factor Cdt1 enable the identification of key residues for binding to replicative helicase Mcm proteins. J Biol Chem. 2010;285:15931-40 pubmed publisher
    ..Our data suggest the possibility that winged-helix domain plays a role as a common module to interact with replicative helicase in the DNA replication-licensing process. ..
  6. 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. ..
  7. 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
  8. Liu C, Wu R, Zhou B, Wang J, Wei Z, Tye B, et al. Structural insights into the Cdt1-mediated MCM2-7 chromatin loading. Nucleic Acids Res. 2012;40:3208-17 pubmed publisher
    ..To elucidate the molecular mechanism of this event, we determined the structure of the human Cdt1-Mcm6 binding domains, the Cdt1(410-440)/MCM6(708-821) complex by NMR...
  9. 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. ..
  10. Bochman M, Schwacha A. The Saccharomyces cerevisiae Mcm6/2 and Mcm5/3 ATPase active sites contribute to the function of the putative Mcm2-7 'gate'. Nucleic Acids Res. 2010;38:6078-88 pubmed publisher
  11. De Piccoli G, Katou Y, Itoh T, Nakato R, Shirahige K, Labib K. Replisome stability at defective DNA replication forks is independent of S phase checkpoint kinases. Mol Cell. 2012;45:696-704 pubmed publisher
  12. Nguyen V, Co C, Irie K, Li J. Clb/Cdc28 kinases promote nuclear export of the replication initiator proteins Mcm2-7. Curr Biol. 2000;10:195-205 pubmed
    ..Such an arrangement could ensure that Mcm proteins complete their replication function before they are removed from the nucleus. ..
  13. Lydeard J, Lipkin Moore Z, Sheu Y, Stillman B, Burgers P, Haber J. Break-induced replication requires all essential DNA replication factors except those specific for pre-RC assembly. Genes Dev. 2010;24:1133-44 pubmed publisher
    ..These results suggest that origin-independent BIR involves cross-talk between normal DNA replication factors and PRR. ..
  14. Aparicio O, Weinstein D, Bell S. Components and dynamics of DNA replication complexes in S. cerevisiae: redistribution of MCM proteins and Cdc45p during S phase. Cell. 1997;91:59-69 pubmed
    ..Our results identify protein components of the pre-RC and a novel replication complex appearing at the G1/S transition (the RC), and suggest that after initiation MCM proteins and Cdc45p move with eukaryotic replication forks. ..
  15. 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
    ..We suggest that DDK docks on and phosphorylates MCM proteins at licensed origins to promote proper assembly of pre-IC. ..
  16. Nedelcheva M, Roguev A, Dolapchiev L, Shevchenko A, Taskov H, Shevchenko A, et al. Uncoupling of unwinding from DNA synthesis implies regulation of MCM helicase by Tof1/Mrc1/Csm3 checkpoint complex. J Mol Biol. 2005;347:509-21 pubmed
    ..In concordance with this suggestion, we found that the Tof1/Csm3/Mrc1 checkpoint complex interacts directly with the MCM helicase during both replication fork progression and when the replication fork is stalled. ..
  17. 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. ..
  18. Weinreich M, Stillman B. Cdc7p-Dbf4p kinase binds to chromatin during S phase and is regulated by both the APC and the RAD53 checkpoint pathway. EMBO J. 1999;18:5334-46 pubmed
    ..Cdc7p-Dbf4p efficiently phosphorylates several proteins that are required for the initiation of DNA replication, including five of the six Mcm proteins and the p180 subunit of DNA polymerase alpha-primase. ..
  19. 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
    ..A three-domain Cdt1 configuration embraces Mcm2, Mcm4, and Mcm6, thus comprising nearly half of the hexamer...
  20. 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. ..
  21. Tsai F, Vijayraghavan S, Prinz J, MacAlpine H, MacAlpine D, Schwacha A. Mcm2-7 Is an Active Player in the DNA Replication Checkpoint Signaling Cascade via Proposed Modulation of Its DNA Gate. Mol Cell Biol. 2015;35:2131-43 pubmed publisher
    ..We infer that this conformational change is required for its DRC role and propose that it allosterically facilitates Rad53 activation to ensure a replication-specific checkpoint response. ..
  22. Komata M, Bando M, Araki H, Shirahige K. The direct binding of Mrc1, a checkpoint mediator, to Mcm6, a replication helicase, is essential for the replication checkpoint against methyl methanesulfonate-induced stress. Mol Cell Biol. 2009;29:5008-19 pubmed publisher
    ..We surveyed replication elongation proteins that interact directly with Mrc1 and identified a replicative helicase, Mcm6, as a specific Mrc1-binding protein...
  23. van Deursen F, Sengupta S, De Piccoli G, Sanchez Diaz A, Labib K. Mcm10 associates with the loaded DNA helicase at replication origins and defines a novel step in its activation. EMBO J. 2012;31:2195-206 pubmed publisher
    ..These findings indicate that Mcm10 is required for a novel step during activation of the Cdc45-MCM-GINS helicase at DNA replication origins. ..
  24. 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
    ..In keeping with this observation, Mcm4/6/7 binds DNA as a hexamer. The minimal functional unit of Mcm4/6/7 is a hexamer. One of the roles of ATP binding by Mcm4/6/7 may be to stabilize formation of hexamers. ..
  25. 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. ..
  26. 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-ΔTPR cells is still CMG specific, highlighting the complex regulation of the final stages of chromosome replication, about which much still remains to be learned. ..
  27. 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
  28. 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...
  29. 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. ..
  30. 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. ..
  31. 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. ..
  32. 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. ..
  33. 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
    ..Moreover, the binding site for Mcm10 on MCM includes the Mcm2 and Mcm6 subunits and overlaps that for the loading factor Cdt1...
  34. 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. ..
  35. 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. ..
  36. Lei M, Kawasaki Y, Young M, Kihara M, Sugino A, Tye B. Mcm2 is a target of regulation by Cdc7-Dbf4 during the initiation of DNA synthesis. Genes Dev. 1997;11:3365-74 pubmed
    ..Taken together, our data suggest that phosphorylation of Mcm2 and probably other members of the Mcm2-7 proteins by Cdc7-Dbf4 at the G1-to-S phase transition is a critical step in the initiation of DNA synthesis at replication origins. ..
  37. 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. ..
  38. 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
    ..Moreover, phosphomimicking mutants in Mcm4 and Mcm6 bind Sld3 without DDK and facilitate DDK-independent replication...
  39. 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 publisher
    ..Finally, constitutive overexpression of each individual MCM subunit was examined, and genotoxic sensitivity was found to be specific to Mcm2 or Mcm4 overexpression, further pointing to the importance of the DDK-MCM ring interaction. ..
  40. Langston L, Zhang D, Yurieva O, Georgescu R, Finkelstein J, Yao N, et al. CMG helicase and DNA polymerase ε 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 ε and CMG provides an explanation for specific targeting of Pol ε to the leading strand and provides clear mechanistic evidence for how strand asymmetry is maintained in eukaryotes. ..
  41. 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. ..
  42. 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. ..
  43. 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. ..
  44. 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. ..
  45. 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. ..
  46. Zou L, Stillman B. Formation of a preinitiation complex by S-phase cyclin CDK-dependent loading of Cdc45p onto chromatin. Science. 1998;280:593-6 pubmed
  47. Dhingra N, Bruck I, Smith S, Ning B, Kaplan D. Dpb11 protein helps control assembly of the Cdc45·Mcm2-7·GINS replication fork helicase. J Biol Chem. 2015;290:7586-601 pubmed publisher
    ..Finally, we propose that Dpb11 functions with Sld2 and Sld3 to help control the assembly of the replication fork helicase. ..
  48. 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. ..
  49. Ma L, Zhai Y, Feng D, Chan T, Lu Y, Fu X, et al. Identification of novel factors involved in or regulating initiation of DNA replication by a genome-wide phenotypic screen in Saccharomyces cerevisiae. Cell Cycle. 2010;9:4399-410 pubmed
    ..These data suggest that Ctf1p and Ctf18p together play important roles in regulating the initiation of DNA replication. ..
  50. García Rodríguez L, De Piccoli G, Marchesi V, Jones R, Edmondson R, Labib K. A conserved Polϵ 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 ϵ at defective replication forks is a key step in activation of the S-phase checkpoint. ..
  51. 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. ..
  52. 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. ..
  53. Liachko I, Tye B. Mcm10 mediates the interaction between DNA replication and silencing machineries. Genetics. 2009;181:379-91 pubmed publisher
    ..Our findings suggest that Mcm10 is required for the coupling of the replication and silencing machineries to silence chromatin in a context outside of DNA replication beyond the recruitment and spreading of Sir2 on chromatin. ..
  54. Lõoke M, Maloney M, Bell S. Mcm10 regulates DNA replication elongation by stimulating the CMG replicative helicase. Genes Dev. 2017;31:291-305 pubmed publisher
    ..Our findings expand the roles of Mcm10 during DNA replication and suggest a new model for Mcm10 function as an activator of the CMG complex throughout DNA replication. ..