Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The CMG helicase and cancer: a tumor “engine” and weakness with missing mutations

Oncogene volume 42, pages 473–490 (2023)Cite this article

Subjects

Abstract

The replicative Cdc45-MCM-GINS (CMG) helicase is a large protein complex that functions in the DNA melting and unwinding steps as a component of replisomes during DNA replication in mammalian cells. Although the CMG performs this important role in cell growth, the CMG is not a simple bystander in cell cycle events. Components of the CMG, specifically the MCM precursors, are also involved in maintaining genomic stability by regulating DNA replication fork speeds, facilitating recovery from replicative stresses, and preventing consequential DNA damage. Given these important functions, MCM/CMG complexes are highly regulated by growth factors such as TGF-ß1 and by signaling factors such as Myc, Cyclin E, and the retinoblastoma protein. Mismanagement of MCM/CMG complexes when these signaling mediators are deregulated, and in the absence of the tumor suppressor protein p53, leads to increased genomic instability and is a contributor to tumorigenic transformation and tumor heterogeneity. The goal of this review is to provide insight into the mechanisms and dynamics by which the CMG is regulated during its assembly and activation in mammalian genomes, and how errors in CMG regulation due to oncogenic changes promote tumorigenesis. Finally, and most importantly, we highlight the emerging understanding of the CMG helicase as an exploitable vulnerability and novel target for therapeutic intervention in cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Structure and assembly of the replicative human CMG helicase.
Fig. 2: Mammalian cells load excessive MCM hexamers onto DNA for multiple purposes.
Fig. 3: Transforming growth factor-ß1 cell cycle arrest signaling pathways target multiple aspects of MCM assembly and CMG activation.
Fig. 4: Oncogenes such as Myc and Cyclin E mismanage the reserve MCM/CMGs.
Fig. 5: Human cancers do not contain known cancer-driver mutations in CMG components.
Fig. 6: Rationale for targeting MCMs/CMGs with anti-cancer drugs.

Similar content being viewed by others

References

  1. Ellenberg J. How not to be wrong: the power of mathematical thinking. The Penguin Press: New York; 2014.

  2. Reed DR, Metts J, Pressley M, Fridley BL, Hayashi M, Isakoff MS, et al. An evolutionary framework for treating pediatric sarcomas. Cancer. 2020;126:2577–87.

    Article  PubMed  Google Scholar 

  3. Reed DR, Alexandrow MG. Myc and the replicative CMG helicase: the creation and destruction of cancer: Myc over-activation of CMG helicases drives tumorigenesis and creates a vulnerability in CMGs for therapeutic intervention. Bioessays. 2020;42:e1900218.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Dominguez-Sola D, Gautier J. MYC and the control of DNA replication. Cold Spring Harb Perspect Med. 2014;4:a014423.

  5. Srinivasan SV, Dominguez-Sola D, Wang LC, Hyrien O, Gautier J. Cdc45 is a critical effector of myc-dependent DNA replication stress. Cell Rep. 2013;3:1629–39.

    Article  CAS  PubMed  Google Scholar 

  6. Dominguez-Sola D, Ying CY, Grandori C, Ruggiero L, Chen B, Li M, et al. Non-transcriptional control of DNA replication by c-Myc. Nature. 2007;448:445–51.

    Article  CAS  PubMed  Google Scholar 

  7. Ekholm-Reed S, Mendez J, Tedesco D, Zetterberg A, Stillman B, Reed SI. Deregulation of cyclin E in human cells interferes with prereplication complex assembly. J Cell Biol. 2004;165:789–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Aparicio T, Ibarra A, Mendez J. Cdc45-MCM-GINS, a new power player for DNA replication. Cell Div. 2006;1:18.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Costa A, Ilves I, Tamberg N, Petojevic T, Nogales E, Botchan MR, et al. The structural basis for MCM2-7 helicase activation by GINS and Cdc45. Nat Struct Mol Biol. 2011;18:471–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ilves I, Petojevic T, Pesavento JJ, Botchan MR. Activation of the MCM2-7 helicase by association with Cdc45 and GINS proteins. Mol Cell. 2010;37:247–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gambus A, Jones RC, Sanchez-Diaz A, Kanemaki M, van Deursen F, Edmondson RD, et al. GINS maintains association of Cdc45 with MCM in replisome progression complexes at eukaryotic DNA replication forks. Nat Cell Biol. 2006;8:358–66.

    Article  CAS  PubMed  Google Scholar 

  12. Miller TCR, Locke J, Greiwe JF, Diffley JFX, Costa A. Mechanism of head-to-head MCM double-hexamer formation revealed by cryo-EM. Nature. 2019;575:704–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Remus D, Beuron F, Tolun G, Griffith JD, Morris EP, Diffley JF. Concerted loading of Mcm2-7 double hexamers around DNA during DNA replication origin licensing. Cell. 2009;139:719–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yao NY, Zhang D, Yurieva O, O’Donnell ME. CMG helicase can use ATPgammaS to unwind DNA: implications for the rate-limiting step in the reaction mechanism. Proc Natl Acad Sci USA. 2022;119:e2119580119.

  15. Yuan Z, Georgescu R, Bai L, Zhang D, Li H, O’Donnell ME. DNA unwinding mechanism of a eukaryotic replicative CMG helicase. Nat Commun. 2020;11:688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yao NY, O’Donnell ME. Getting ready for DNA duplication. Elife. 2019;8:e51291.

  17. O’Donnell ME, Li H. The ring-shaped hexameric helicases that function at DNA replication forks. Nat Struct Mol Biol. 2018;25:122–30.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Li H, O’Donnell ME. The eukaryotic CMG helicase at the replication fork: emerging architecture reveals an unexpected mechanism. Bioessays. 2018;40.

  19. Eickhoff P, Kose HB, Martino F, Petojevic T, Abid Ali F, Locke J, et al. Molecular basis for ATP-hydrolysis-driven DNA translocation by the CMG helicase of the eukaryotic replisome. Cell Rep. 2019;28:2673–88.e2678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kang S, Warner MD, Bell SP. Multiple functions for Mcm2-7 ATPase motifs during replication initiation. Mol Cell. 2014;55:655–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu L, Zhang Y, Zhang J, Wang JH, Cao Q, Li Z, et al. Characterization of the dimeric CMG/pre-initiation complex and its transition into DNA replication forks. Cell Mol Life Sci. 2020;77:3041–58.

    Article  CAS  PubMed  Google Scholar 

  22. Bell SP. DNA replication. Terminating the replisome. Science. 2014;346:418–9.

    Article  CAS  PubMed  Google Scholar 

  23. Lewis JS, Gross MH, Sousa J, Henrikus SS, Greiwe JF, Nans A, et al. Mechanism of replication origin melting nucleated by CMG helicase assembly. Nature. 2022;606:1007–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Costa A, Diffley JFX. The initiation of eukaryotic DNA replication. Annu Rev Biochem. 2022;91:107–31.

    Article  PubMed  Google Scholar 

  25. Usman M, Okla MK, Asif HM, AbdElgayed G, Muccee F, Ghazanfar S, et al. A pan-cancer analysis of GINS complex subunit 4 to identify its potential role as a biomarker in multiple human cancers. Am J Cancer Res. 2022;12:986–1008.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. He Z, Wang X, Yang Z, Jiang Y, Li L, Wang X, et al. Expression and prognosis of CDC45 in cervical cancer based on the GEO database. PeerJ. 2021;9:e12114.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhang K, Zhou J, Wu T, Tian Q, Liu T, Wang W, et al. Combined analysis of expression, prognosis and immune infiltration of GINS family genes in human sarcoma. Aging (Albany NY). 2022;14:5895–907.

    Article  CAS  PubMed  Google Scholar 

  28. Yu S, Wang G, Shi Y, Xu H, Zheng Y, Chen Y. MCMs in cancer: prognostic potential and mechanisms. Anal Cell Pathol (Amst). 2020;2020:3750294.

    PubMed  Google Scholar 

  29. Rzechorzek NJ, Hardwick SW, Jatikusumo VA, Chirgadze DY, Pellegrini L. CryoEM structures of human CMG-ATPgammaS-DNA and CMG-AND-1 complexes. Nucleic Acids Res. 2020;48:6980–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bochman ML, Schwacha A. The Mcm2-7 complex has in vitro helicase activity. Mol Cell. 2008;31:287–93.

    Article  CAS  PubMed  Google Scholar 

  31. Pacek M, Tutter AV, Kubota Y, Takisawa H, Walter JC. Localization of MCM2-7, Cdc45, and GINS to the site of DNA unwinding during eukaryotic DNA replication. Mol Cell. 2006;21:581–7.

    Article  CAS  PubMed  Google Scholar 

  32. Pacek M, Walter JC. A requirement for MCM7 and Cdc45 in chromosome unwinding during eukaryotic DNA replication. EMBO J. 2004;23:3667–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Botchan M, Berger J. DNA replication: making two forks from one prereplication complex. Mol Cell. 2010;40:860–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Deegan TD, Mukherjee PP, Fujisawa R, Polo Rivera C, Labib K. CMG helicase disassembly is controlled by replication fork DNA, replisome components and a ubiquitin threshold. Elife. 2020;9:e60371.

  35. Yeeles JTP, Janska A, Early A, Diffley JFX. How the eukaryotic replisome achieves rapid and efficient DNA replication. Mol Cell. 2017;65:105–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Georgescu R, Yuan Z, Bai L, de Luna Almeida Santos R, Sun J, Zhang D, et al. Structure of eukaryotic CMG helicase at a replication fork and implications to replisome architecture and origin initiation. Proc Natl Acad Sci USA. 2017;114:E697–E706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gambus A, van Deursen F, Polychronopoulos D, Foltman M, Jones RC, Edmondson RD, et al. A key role for Ctf4 in coupling the MCM2-7 helicase to DNA polymerase alpha within the eukaryotic replisome. EMBO J. 2009;28:2992–3004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bryant VL, Elias RM, McCarthy SM, Yeatman TJ, Alexandrow MG. Suppression of reserve MCM complexes chemosensitizes to gemcitabine and 5-fluorouracil. Mol Cancer Res. 2015;13:1296–305.

  39. Ibarra A, Schwob E, Mendez J. Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication. Proc Natl Acad Sci USA. 2008;105:8956–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ge XQ, Jackson DA, Blow JJ. Dormant origins licensed by excess Mcm2-7 are required for human cells to survive replicative stress. Genes Dev. 2007;21:3331–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Woodward AM, Gohler T, Luciani MG, Oehlmann M, Ge X, Gartner A, et al. Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress. J Cell Biol. 2006;173:673–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Coster G, Frigola J, Beuron F, Morris EP, Diffley JF. Origin licensing requires ATP binding and hydrolysis by the MCM replicative helicase. Mol Cell. 2014;55:666–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tanaka S, Diffley JF. Interdependent nuclear accumulation of budding yeast Cdt1 and Mcm2-7 during G1 phase. Nat Cell Biol. 2002;4:198–207.

    Article  CAS  PubMed  Google Scholar 

  44. Labib K, Kearsey SE, Diffley JF. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Donovan S, Harwood J, Drury LS, Diffley JFX. Cdc6p-dependent loading of Mcm proteins onto pre-replicative chromatin in budding yeast. Proc Natl Acad Sci USA. 1997;94:5611–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Austin RJ, Orr-Weaver TL, Bell SP. Drosophila ORC specifically binds to ACE3, an origin of DNA replication control element. Genes Dev. 1999;13:2639–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bell SP, Mitchell J, Leber J, Kobayashi R, Stillman B. The multidomain structure of Orc1p reveals similarity to regulators of DNA replication and transcriptional silencing. Cell. 1995;83:563–8.

    Article  CAS  PubMed  Google Scholar 

  48. Santocanale C, Diffley JFX. ORC- and Cdc6-dependent complexes at active and inactive chromosomal replication origins in Saccharomyces cerevisiae. EMBO J. 1996;15:6671–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liang C, Weinreich M, Stillman B. ORC and Cdc6p interact and determine the frequency of initiation of DNA replication in the genome. Cell. 1995;81:667–76.

    Article  CAS  PubMed  Google Scholar 

  50. Madine MA, Swietlik M, Pelizon C, Romanowski P, Mills AD, Laskey RA. The roles of the MCM, ORC, and Cdc6 proteins in determining the replication competence of chromatin in quiescent cells. J Struct Biol. 2000;129:198–210.

    Article  CAS  PubMed  Google Scholar 

  51. Frigola J, Remus D, Mehanna A, Diffley JF. ATPase-dependent quality control of DNA replication origin licensing. Nature. 2013;495:339–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Edwards MC, Tutter AV, Cvetic C, Gilbert CH, Prokhorova TA, Walter JC. MCM2-7 complexes bind chromatin in a distributed pattern surrounding the origin recognition complex in Xenopus egg extracts. J Biol Chem. 2002;277:33049–57.

    Article  CAS  PubMed  Google Scholar 

  53. Bell SP, Stillman B. ATP-dependent recognition of eukaryotic origins of DNA replication by a multiprotein complex. Nature. 1992;357:128–34.

    Article  CAS  PubMed  Google Scholar 

  54. Fernandez-Cid A, Riera A, Tognetti S, Herrera MC, Samel S, Evrin C, et al. An ORC/Cdc6/MCM2-7 complex is formed in a multistep reaction to serve as a platform for MCM double-hexamer assembly. Mol Cell. 2013;50:577–88.

    Article  CAS  PubMed  Google Scholar 

  55. Gavin KA, Hidaka M, Stillman B. Conserved initiator proteins in eukaryotes. Science. 1995;270:1667–71.

    Article  CAS  PubMed  Google Scholar 

  56. Rowley A, Cocker JH, Harwood J, Diffley JFX. Initiation complex assembly at budding yeast replication origins begins with the recognition of a bipartite sequence by limiting amounts of the initiator, ORC. EMBO J. 1995;14:2631–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chesnokov I, Gossen M, Remus D, Botchan M. Assembly of functionally active Drosophila origin recognition complex from recombinant proteins. Genes Dev. 1999;13:1289–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Remus D, Beall EL, Botchan MR. DNA topology, not DNA sequence, is a critical determinant for Drosophila ORC-DNA binding. EMBO J. 2004;23:897–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cvetic C, Walter JC. Eukaryotic origins of DNA replication: could you please be more specific? Semin Cell Dev Biol. 2005;16:343–53.

    Article  CAS  PubMed  Google Scholar 

  60. Vashee S, Cvetic C, Lu W, Simancek P, Kelly TJ, Walter JC. Sequence-independent DNA binding and replication initiation by the human origin recognition complex. Genes Dev. 2003;17:1894–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hamlin JL, Mesner LD, Dijkwel PA. A winding road to origin discovery. Chromosome Res. 2010;18:45–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hamlin JL, Mesner LD, Lar O, Torres R, Chodaparambil SV, Wang L. A revisionist replicon model for higher eukaryotic genomes. J Cell Biochem. 2008;105:321–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Klemm RD, Austin RJ, Bell SP. Coordinate binding of ATP and origin DNA regulates the ATPase activity of the origin recognition complex. Cell. 1997;88:493–502.

    Article  CAS  PubMed  Google Scholar 

  64. Lee DG, Makhov AM, Klemm RD, Griffith JD, Bell SP. Regulation of origin recognition complex conformation and ATPase activity: differential effects of single-stranded and double-stranded DNA binding. EMBO J. 2000;19:4774–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Weinreich M, Liang C, Stillman B. The Cdc6p nucleotide-binding motif is required for loading mcm proteins onto chromatin. Proc Natl Acad Sci USA. 1999;96:441–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Perkins G, Diffley JFX. Nucleotide-dependent prereplicative complex assembly by Cdc6p, a homolog of eukaryotic and prokaryotic clamp-loaders. Mol Cell. 1998;2:23–32.

    Article  CAS  PubMed  Google Scholar 

  67. Blow JJ, Hodgson B. Replication licensing-defining the proliferative state? Trends Cell Biol. 2002;12:72–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tada S, Blow JJ. The replication licensing system. Biol Chem. 1998;379:941–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Thommes P, Kubota Y, Takisawa H, Blow JJ. The RLF-M component of the replication licensing system forms complexes containing all six MCM/P1 polypeptides. EMBO J. 1997;16:3312–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chong JP, Blow JJ. DNA replication licensing factor. Prog Cell Cycle Res. 1996;2:83–90.

    Article  CAS  PubMed  Google Scholar 

  71. Chong JPJ, Mahbubani HM, Khoo C-Y, Blow JJ. Purification of an MCM-containing complex as a component of the DNA replication licensing system. Nature. 1995;375:418–21.

    Article  CAS  PubMed  Google Scholar 

  72. Cvetic CA, Walter JC. Getting a grip on licensing: mechanism of stable Mcm2-7 loading onto replication origins. Mol Cell. 2006;21:143–4.

    Article  CAS  PubMed  Google Scholar 

  73. Cocker JH, Piatti S, Santocanale C, Nasmyth K, Diffley JFX. An essential role for the Cdc6 protein in forming the pre-replicative complexes of budding yeast. Nature. 1996;379:180–2.

    Article  CAS  PubMed  Google Scholar 

  74. Cook JG, Park CH, Burke TW, Leone G, DeGregori J, Engel A, et al. Analysis of Cdc6 function in the assembly of mammalian prereplication complexes. Proc Natl Acad Sci USA. 2002;99:1347–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yan Z, DeGregori J, Shohet R, Leone G, Stillman B, Nevins JR, et al. Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells. Proc Natl Acad Sci USA. 1998;95:3603–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Furstenthal L, Kaiser BK, Swanson C, Jackson PK. Cyclin E uses Cdc6 as a chromatin-associated receptor required for DNA replication. J Cell Biol. 2001;152:1267–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nepon-Sixt BS, Alexandrow MG. TGFbeta1 cell cycle arrest is mediated by inhibition of MCM assembly in Rb-deficient conditions. Mol Cancer Res. 2019;17:277–88.

    Article  PubMed  Google Scholar 

  78. Geng Y, Lee YM, Welcker M, Swanger J, Zagozdzon A, Winer JD, et al. Kinase-independent function of cyclin E. Mol Cell. 2007;25:127–39.

    Article  CAS  PubMed  Google Scholar 

  79. Saha P, Chen J, Thome KC, Lawlis SJ, Hou ZH, Hendricks M, et al. Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase. Mol Cell Biol. 1998;18:2758–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Alexandrow MG, Hamlin JL. Cdc6 chromatin affinity is unaffected by serine-54 phosphorylation, S-phase progression, and overexpression of cyclin A. Mol Cell Biol. 2004;24:1614–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lau E, Zhu C, Abraham RT, Jiang W. The functional role of Cdc6 in S-G2/M in mammalian cells. EMBO Rep. 2006;7:425–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Walter D, Hoffmann S, Komseli ES, Rappsilber J, Gorgoulis V, Sorensen CS. SCF(Cyclin F)-dependent degradation of CDC6 suppresses DNA re-replication. Nat Commun. 2016;7:10530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Mailand N, Diffley JF. CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis. Cell. 2005;122:915–26.

    Article  CAS  PubMed  Google Scholar 

  84. Li J, Deng M, Wei Q, Liu T, Tong X, Ye X. Phosphorylation of MCM3 protein by cyclin E/cyclin-dependent kinase 2 (Cdk2) regulates its function in cell cycle. J Biol Chem. 2011;286:39776–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wei Q, Li J, Liu T, Tong X, Ye X. Phosphorylation of minichromosome maintenance protein 7 (MCM7) by cyclin/cyclin-dependent kinase affects its function in cell cycle regulation. J Biol Chem. 2013;288:19715–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hendrickson M, Madine M, Dalton S, Gautier J. Phosphorylation of MCM4 by cdc2 protein kinase inhibits the activity of the minichromosome maintenance complex. Proc Natl Acad Sci USA. 1996;93:12223–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Moritani M, Ishimi Y. Inhibition of DNA binding of MCM2-7 complex by phosphorylation with cyclin-dependent kinases. J Biochem. 2013;154:363–72.

    Article  CAS  PubMed  Google Scholar 

  88. Findeisen M, El-Denary M, Kapitza T, Graf R, Strausfeld U. Cyclin A-dependent kinase activity affects chromatin binding of ORC, Cdc6, and MCM in egg extracts of Xenopus laevis. Eur J Biochem. 1999;264:415–26.

    Article  CAS  PubMed  Google Scholar 

  89. Boos D, Sanchez-Pulido L, Rappas M, Pearl LH, Oliver AW, Ponting CP, et al. Regulation of DNA replication through Sld3-Dpb11 interaction is conserved from yeast to humans. Curr Biol. 2011;21:1152–7.

    Article  CAS  PubMed  Google Scholar 

  90. Kumagai A, Shevchenko A, Shevchenko A, Dunphy WG. Treslin collaborates with TopBP1 in triggering the initiation of DNA replication. Cell. 2010;140:349–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kumagai A, Shevchenko A, Shevchenko A, Dunphy WG. Direct regulation of Treslin by cyclin-dependent kinase is essential for the onset of DNA replication. J Cell Biol. 2011;193:995–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Mukherjee P, Cao TV, Winter SL, Alexandrow MG. Mammalian MCM loading in late-G(1) coincides with Rb hyperphosphorylation and the transition to post-transcriptional control of progression into S-phase. PLoS One. 2009;4:e5462.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol. 1995;15:2612–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Dou Q-P, Levin AH, Zhao S, Pardee AB. Cyclin E and cyclin A as candidates for the restriction point protein. Cancer Res. 1993;53:1493–7.

    CAS  PubMed  Google Scholar 

  95. Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, et al. Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science. 1992;257:1689–94.

    Article  CAS  PubMed  Google Scholar 

  96. Koff A, Cross F, Fisher A, Schumacher J, Leguellec K, Philippe M, et al. Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family. Cell. 1991;66:1217–28.

    Article  CAS  PubMed  Google Scholar 

  97. Dulic V, Lees E, Reed SI. Association of human cyclin E with a periodic G1-S phase protein kinase. Science. 1992;257:1958–61.

    Article  CAS  PubMed  Google Scholar 

  98. Lundberg AS, Weinberg RA. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol Cell Biol. 1998;18:753–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Keenan SM, Lents NH, Baldassare JJ. Expression of cyclin E renders cyclin D-CDK4 dispensable for inactivation of the retinoblastoma tumor suppressor protein, activation of E2F, and G1-S phase progression. J Biol Chem. 2004;279:5387–96.

    Article  CAS  PubMed  Google Scholar 

  100. Mendez J, Stillman B. Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis. Mol Cell Biol. 2000;20:8602–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhang J, Yu L, Wu X, Zou L, Sou KK, Wei Z, et al. The interacting domains of hCdt1 and hMcm6 involved in the chromatin loading of the MCM complex in human cells. Cell Cycle. 2010;9:4848–57.

    Article  CAS  PubMed  Google Scholar 

  102. Wei Z, Liu C, Wu X, Xu N, Zhou B, Liang C, et al. Characterization and structure determination of the Cdt1 binding domain of human minichromosome maintenance (Mcm) 6. The. J Biol Chem. 2010;285:12469–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Liu C, Wu R, Zhou B, Wang J, Wei Z, Tye BK, et al. Structural insights into the Cdt1-mediated MCM2-7 chromatin loading. Nucleic Acids Res. 2012;40:3208–17.

    Article  CAS  PubMed  Google Scholar 

  104. 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;24:316–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yanagi K, Mizuno T, You Z, Hanaoka F. Mouse geminin inhibits not only Cdt1-MCM6 interactions but also a novel intrinsic Cdt1 DNA binding activity. J Biol Chem. 2002;277:40871–80.

    Article  CAS  PubMed  Google Scholar 

  106. Saxena S, Dutta A. Geminin-Cdt1 balance is critical for genetic stability. Mutat Res. 2005;569:111–21.

    Article  CAS  PubMed  Google Scholar 

  107. Hodgson B, Li A, Tada S, Blow JJ. Geminin becomes activated as an inhibitor of Cdt1/RLF-B following nuclear import. Curr Biol. 2002;12:678–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Madine M, Laskey R. Geminin bans replication licence. Nat Cell Biol. 2001;3:E49–50.

    Article  CAS  PubMed  Google Scholar 

  109. Wohlschlegel JA, Dwyer BT, Dhar SK, Cvetic C, Walter JC, Dutta A. Inhibition of eukaryotic DNA replication by geminin binding to Cdt1. Science. 2000;290:2309–12.

    Article  CAS  PubMed  Google Scholar 

  110. Wong PG, Glozak MA, Cao TV, Vaziri C, Seto E, Alexandrow M. Chromatin unfolding by Cdt1 regulates MCM loading via opposing functions of HBO1 and HDAC11-geminin. Cell Cycle. 2010;9:4351–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Miotto B, Struhl K. HBO1 histone acetylase is a coactivator of the replication licensing factor Cdt1. Genes Dev. 2008;22:2633–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Iizuka M, Matsui T, Takisawa H, Smith MM. Regulation of replication licensing by acetyltransferase Hbo1. Mol Cell Biol. 2006;26:1098–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Iizuka M, Stillman B. Histone acetyltransferase HBO1 interacts with the ORC1 subunit of the human initiator protein. J Biol Chem. 1999;274:23027–34.

    Article  CAS  PubMed  Google Scholar 

  114. Miotto B, Struhl K. HBO1 histone acetylase activity is essential for DNA replication licensing and inhibited by Geminin. Mol Cell. 2010;37:57–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Vaziri C, Saxena S, Jeon Y, Lee C, Murata K, Machida Y, et al. A p53-dependent checkpoint pathway prevents rereplication. Mol Cell. 2003;11:997–1008.

    Article  CAS  PubMed  Google Scholar 

  116. Arentson E, Faloon P, Seo J, Moon E, Studts JM, Fremont DH, et al. Oncogenic potential of the DNA replication licensing protein CDT1. Oncogene. 2002;21:1150–8.

    Article  CAS  PubMed  Google Scholar 

  117. Seo J, Chung YS, Sharma GG, Moon E, Burack WR, Pandita TK, et al. Cdt1 transgenic mice develop lymphoblastic lymphoma in the absence of p53. Oncogene. 2005;24:8176–86.

    Article  CAS  PubMed  Google Scholar 

  118. Walter JC. Evidence for sequential action of cdc7 and cdk2 protein kinases during initiation of DNA replication in Xenopus egg extracts. J Biol Chem. 2000;275:39773–8.

    Article  CAS  PubMed  Google Scholar 

  119. Lin XH, Walter J, Scheidtmann K, Ohst K, Newport J, Walter G. Protein phosphatase 2A is required for the initiation of chromosomal DNA replication. Proc Natl Acad Sci USA. 1998;95:14693–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ballabeni A, Zamponi R, Caprara G, Melixetian M, Bossi S, Masiero L, et al. Human CDT1 associates with CDC7 and recruits CDC45 to chromatin during S phase. J Biol Chem. 2009;284:3028–36.

    Article  CAS  PubMed  Google Scholar 

  121. Chou DM, Petersen P, Walter JC, Walter G. Protein phosphatase 2A regulates binding of Cdc45 to the prereplication complex. J Biol Chem. 2002;277:40520–7.

    Article  CAS  PubMed  Google Scholar 

  122. Greiwe JF, Miller TCR, Locke J, Martino F, Howell S, Schreiber A, et al. Structural mechanism for the selective phosphorylation of DNA-loaded MCM double hexamers by the Dbf4-dependent kinase. Nat Struct Mol Biol. 2022;29:10–20.

    Article  CAS  PubMed  Google Scholar 

  123. Yeeles JT, Deegan TD, Janska A, Early A, Diffley JF. Regulated eukaryotic DNA replication origin firing with purified proteins. Nature. 2015;519:431–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Mukherjee P, Winter SL, Alexandrow MG. Cell cycle arrest by transforming growth factor beta1 near G1/S is mediated by acute abrogation of prereplication complex activation involving an Rb-MCM interaction. Mol Cell Biol. 2010;30:845–56.

    Article  CAS  PubMed  Google Scholar 

  125. Kang YH, Galal WC, Farina A, Tappin I, Hurwitz J. Properties of the human Cdc45/Mcm2-7/GINS helicase complex and its action with DNA polymerase epsilon in rolling circle DNA synthesis. Proc Natl Acad Sci USA. 2012;109:6042–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Baretic D, Jenkyn-Bedford M, Aria V, Cannone G, Skehel M, Yeeles JTP. Cryo-EM structure of the fork protection complex bound to CMG at a replication fork. Mol Cell. 2020;78:926–40.e913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kang YH, Farina A, Bermudez VP, Tappin I, Du F, Galal WC, et al. Interaction between human Ctf4 and the Cdc45/Mcm2-7/GINS (CMG) replicative helicase. Proc Natl Acad Sci USA. 2013;110:19760–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Dmowski M, Jedrychowska M, Makiela-Dzbenska K, Denkiewicz-Kruk M, Sharma S, Chabes A, et al. Increased contribution of DNA polymerase delta to the leading strand replication in yeast with an impaired CMG helicase complex. DNA Repair (Amst). 2022;110:103272.

    Article  CAS  PubMed  Google Scholar 

  129. Baxley RM, Bielinsky AK. Mcm10: a dynamic scaffold at eukaryotic replication forks. Genes (Basel). 2017;8:73.

  130. Mayle R, Langston L, Molloy KR, Zhang D, Chait BT, O’Donnell ME. Mcm10 has potent strand-annealing activity and limits translocase-mediated fork regression. Proc Natl Acad Sci USA. 2019;116:798–803.

    Article  CAS  PubMed  Google Scholar 

  131. Langston LD, Mayle R, Schauer GD, Yurieva O, Zhang D, Yao NY, et al. Mcm10 promotes rapid isomerization of CMG-DNA for replisome bypass of lagging strand DNA blocks. Elife. 2017;6:e29118.

  132. Ricke RM, Bielinsky AK. Mcm10 regulates the stability and chromatin association of DNA polymerase-alpha. Mol Cell. 2004;16:173–85.

    Article  CAS  PubMed  Google Scholar 

  133. Izumi M, Yanagi K, Mizuno T, Yokoi M, Kawasaki Y, Moon KY, et al. The human homolog of Saccharomyces cerevisiae Mcm10 interacts with replication factors and dissociates from nuclease-resistant nuclear structures in G(2) phase. Nucleic Acids Res. 2000;28:4769–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Homesley L, Lei M, Kawasaki Y, Sawyer S, Christensen T, Tye BK. Mcm10 and the MCM2-7 complex interact to initiate DNA synthesis and to release replication factors from origins. Genes Dev. 2000;14:913–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wohlschlegel JA, Dhar SK, Prokhorova TA, Dutta A, Walter JC. Xenopus Mcm10 binds to origins of DNA replication after Mcm2-7 and stimulates origin binding of Cdc45. Mol Cell. 2002;9:233–40.

    Article  CAS  PubMed  Google Scholar 

  136. Douglas ME, Diffley JF. Recruitment of Mcm10 to sites of replication initiation requires direct binding to the minichromosome maintenance (MCM) complex. J Biol Chem. 2016;291:5879–88.

    Article  CAS  PubMed  Google Scholar 

  137. Alexandrow MG, Hamlin JL. Chromatin decondensation in S-phase involves recruitment of Cdk2 by Cdc45 and histone H1 phosphorylation. J Cell Biol. 2005;168:875–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Wong PG, Winter SL, Zaika E, Cao TV, Oguz U, Koomen JM, et al. Cdc45 limits replicon usage from a low density of preRCs in mammalian cells. PLoS One. 2011;6:e17533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Sedlackova H, Rask MB, Gupta R, Choudhary C, Somyajit K, Lukas J. Equilibrium between nascent and parental MCM proteins protects replicating genomes. Nature. 2020;587:297–302.

    Article  CAS  PubMed  Google Scholar 

  140. Huberman JA. Prokaryotic and eukaryotic replicons. Cell. 1995;82:535–42.

    Article  CAS  PubMed  Google Scholar 

  141. Berezney R, Dubey DD, Huberman JA. Heterogeneity of eukaryotic replicons, replicon clusters, and replication foci. Chromosoma. 2000;108:471–84.

    Article  CAS  PubMed  Google Scholar 

  142. Luciani MG, Oehlmann M, Blow JJ. Characterization of a novel ATR-dependent, Chk1-independent, intra-S-phase checkpoint that suppresses initiation of replication in Xenopus. J Cell Sci. 2004;117:6019–30.

    Article  CAS  PubMed  Google Scholar 

  143. Costanzo V, Shechter D, Lupardus PJ, Cimprich KA, Gottesman M, Gautier J. An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication. Mol Cell. 2003;11:203–13.

    Article  CAS  PubMed  Google Scholar 

  144. Shechter D, Gautier J. ATM and ATR check in on origins: a dynamic model for origin selection and activation. Cell Cycle. 2005;4:235–8.

    Article  CAS  PubMed  Google Scholar 

  145. Shechter D, Costanzo V, Gautier J. ATR and ATM regulate the timing of DNA replication origin firing. Nat Cell Biol. 2004;6:648–55.

    Article  CAS  PubMed  Google Scholar 

  146. Shechter D, Costanzo V, Gautier J. Regulation of DNA replication by ATR: signaling in response to DNA intermediates. DNA Repair (Amst). 2004;3:901–8.

    Article  CAS  PubMed  Google Scholar 

  147. Dijkwel PA, Wang S, Hamlin JL. Initiation sites are distributed at frequent intervals in the Chinese hamster dihydrofolate reductase origin of replication but are used with very different efficiencies. Mol Cell Biol. 2002;22:3053–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Dijkwel PA, Hamlin JL. The Chinese hamster dihydrofolate reductase origin consists of multiple potential nascent-strand start sites. Mol Cell Biol. 1995;15:3023–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Dijkwel PA, Vaughn JP, Hamlin JL. Replication initiation sites are distributed widely in the amplified CHO dihydrofolate reductase domain. Nucleic Acids Res. 1994;22:4989–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Hamlin JL, Mosca PJ, Dijkwel PA, Lin H-B. Initiation of replication at a mammalian chromosomal origin. Cold Spring Harb Symp Quant Biol. 1993;58:467–74.

    Article  CAS  PubMed  Google Scholar 

  151. Vaughn JP, Dijkwel PA, Hamlin JL. Replication initiates in a broad zone in the amplified CHO dihydrofolate reductase domain. Cell. 1990;61:1075–87.

    Article  CAS  PubMed  Google Scholar 

  152. Mesner LD, Valsakumar V, Karnani N, Dutta A, Hamlin JL, Bekiranov S. Bubble-chip analysis of human origin distributions demonstrates on a genomic scale significant clustering into zones and significant association with transcription. Genome Res. 2011;21:377–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Alexandrow MG, Ritzi M, Pemov A, Hamlin JL. A potential role for mini-chromosome maintenance (MCM) proteins in initiation at the dihydrofolate reductase replication origin. J Biol Chem. 2002;277:2702–8.

    Article  CAS  PubMed  Google Scholar 

  154. Saha S, Shan Y, Mesner LD, Hamlin JL. The promoter of the Chinese hamster ovary dihydrofolate reductase gene regulates the activity of the local origin and helps define its boundaries. Genes Dev. 2004;18:397–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Mesner LD, Hamlin JL. Specific signals at the 3’ end of the DHFR gene define one boundary of the downstream origin of replication. Genes Dev. 2005;19:1053–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Tippens ND, Liang J, Leung AK, Wierbowski SD, Ozer A, Booth JG, et al. Transcription imparts architecture, function and logic to enhancer units. Nat Genet. 2020;52:1067–75.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Henriques T, Scruggs BS, Inouye MO, Muse GW, Williams LH, Burkholder AB, et al. Widespread transcriptional pausing and elongation control at enhancers. Genes Dev. 2018;32:26–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Comoglio F, Schlumpf T, Schmid V, Rohs R, Beisel C, Paro R. High-resolution profiling of Drosophila replication start sites reveals a DNA shape and chromatin signature of metazoan origins. Cell Rep. 2015;11:821–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. MacAlpine DM, Rodriguez HK, Bell SP. Coordination of replication and transcription along a Drosophila chromosome. Genes Dev. 2004;18:3094–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Karnani N, Taylor CM, Malhotra A, Dutta A. Genomic study of replication initiation in human chromosomes reveals the influence of transcription regulation and chromatin structure on origin selection. Mol Biol Cell. 2010;21:393–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Dellino GI, Cittaro D, Piccioni R, Luzi L, Banfi S, Segalla S, et al. Genome-wide mapping of human DNA-replication origins: levels of transcription at ORC1 sites regulate origin selection and replication timing. Genome Res. 2013;23:1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Chen YH, Keegan S, Kahli M, Tonzi P, Fenyo D, Huang TT, et al. Transcription shapes DNA replication initiation and termination in human cells. Nat Struct Mol Biol. 2019;26:67–77.

    Article  CAS  PubMed  Google Scholar 

  163. Moses HL, Yang EY, Pietenpol JA. Regulation of epithelial proliferation by TGF-beta. Ciba Found Symp. 1991;157:66–74.

    CAS  PubMed  Google Scholar 

  164. Bierie B, Moses HL. TGF-beta and cancer. Cytokine Growth Factor Rev. 2006;17:29–40.

    Article  CAS  PubMed  Google Scholar 

  165. Murphy CS, Pietenpol JA, Munger K, Howley PM, Moses HL. c-myc and pRB: Role in TGFb1 inhibition of keratinocyte proliferation. Cold Spring Harb Symp Quant Biol. 1991;56:129–35.

    Article  CAS  PubMed  Google Scholar 

  166. Massague J. TGFbeta in cancer. Cell. 2008;134:215–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Massague J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000;103:295–309.

    Article  CAS  PubMed  Google Scholar 

  168. Koff A, Ohtsuki M, Polyak K, Roberts JM, Massagué J. Negative regulation of G1 in mammalian cells: Inhibition of cyclin E-dependent kinase by TGF-b. Science. 1993;260:536–9.

    Article  CAS  PubMed  Google Scholar 

  169. Ewen ME, Sluss HK, Whitehouse LL, Livingston DM. TGFb inhibition of Cdk4 synthesis is linked to cell cycle arrest. Cell. 1993;74:1009–20.

    Article  CAS  PubMed  Google Scholar 

  170. Pietenpol JA, Holt JT, Stein RW, Moses HL. Transforming growth factor b-1 suppression of c-myc gene transcription: role in inhibition of keratinocyte proliferation. Proc Natl Acad Sci USA. 1990;87:3758–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Massague J, Chen YG. Controlling TGF-beta signaling. Genes Dev. 2000;14:627–44.

    Article  CAS  PubMed  Google Scholar 

  172. Iavarone A, Massague J. Repression of the Cdk activator Cdc25A and cell cycle arrest by cytokine TGF-b in cells lacking the Cdk inhibitor p15. Nature. 1997;387:417–22.

    Article  CAS  PubMed  Google Scholar 

  173. Reynisdottir I, Polyak K, Iavarone A, Massague J. Kip/Cip and ink4 cdk inhibitors cooperate to induce cell cycle arrest in response to TGFb. Genes Dev. 1995;9:1831–45.

    Article  CAS  PubMed  Google Scholar 

  174. Polyak K, Lee M-H, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell. 1994;78:59–66.

    Article  CAS  PubMed  Google Scholar 

  175. Polyak K, Kato J, Solomon MJ, Sherr CJ, Massague J, Roberts JM, et al. p27Kip1, A cyclin-Cdk inhibitor, links transforming growth factor-b and contact inhibition to cell cycle arrest. Genes Dev. 1994;8:9–22.

    Article  CAS  PubMed  Google Scholar 

  176. Seoane J, Pouponnot C, Staller P, Schader M, Eilers M, Massague J. TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nat Cell Biol. 2001;3:400–8.

    Article  CAS  PubMed  Google Scholar 

  177. Alexandrow MG, Moses HL. Kips off to Myc: implications for TGF beta signaling. J Cell Biochem. 1997;66:427–32.

    Article  CAS  PubMed  Google Scholar 

  178. Pietenpol JA, Stein RW, Moran E, Yaciuk P, Schlegel R, Lyons RM, et al. TGF-b1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains. Cell. 1990;61:777–85.

    Article  CAS  PubMed  Google Scholar 

  179. Laiho M, DeCaprio JA, Ludlow JW, Livingston DM, Massague J. Growth inhibition by TGF-beta linked to suppression of retinoblastoma protein phosphorylation. Cell. 1990;62:175–85.

    Article  CAS  PubMed  Google Scholar 

  180. Wolfraim LA, Walz TM, James Z, Fernandez T, Letterio JJ. p21Cip1 and p27Kip1 act in synergy to alter the sensitivity of naive T cells to TGF-beta-mediated G1 arrest through modulation of IL-2 responsiveness. J Immunol. 2004;173:3093–102.

    Article  CAS  PubMed  Google Scholar 

  181. Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, et al. Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell. 1996;85:707–20.

    Article  CAS  PubMed  Google Scholar 

  182. Voss M, Wolff B, Savitskaia N, Ungefroren H, Deppert W, Schmiegel W, et al. TGFbeta-induced growth inhibition involves cell cycle inhibitor p21 and pRb independent from p15 expression. Int J Oncol. 1999;14:93–101.

    CAS  PubMed  Google Scholar 

  183. Baldwin RL, Korc M. Growth inhibition of human pancreatic carcinoma cells by transforming growth factor beta-1. Growth Factors. 1993;8:23–34.

    Article  CAS  PubMed  Google Scholar 

  184. Alexandrow MG, Kawabata M, Aakre M, Moses HL. Overexpression of the c-Myc oncoprotein blocks the growth-inhibitory response but is required for the mitogenic effects of transforming growth factor beta 1. Proc Natl Acad Sci USA. 1995;92:3239–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Claassen GF, Hann SR. A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor beta -induced cell-cycle arrest. Proc Natl Acad Sci USA. 2000;97:9498–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Sun P, Dong P, Dai K, Hannon GJ, Beach D. p53-independent role of MDM2 in TGF-b1 resistance. Science. 1998;282:2270–2.

    Article  CAS  PubMed  Google Scholar 

  187. Borysov SI, Nepon-Sixt BS, Alexandrow MG. The N-terminus of the Rb protein inhibits DNA replication via a bipartite mechanism disrupted in partially penetrant retinoblastomas. Mol Cell Biol. 2016;36:832–45.

  188. Sterner JM, Dew-Knight S, Musahl C, Kornbluth S, Horowitz JM. Negative regulation of DNA replication by the retinoblastoma protein is mediated by its association with MCM7. Mol Cell Biol. 1998;18:2748–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Hassler M, Singh S, Yue WW, Luczynski M, Lakbir R, Sanchez-Sanchez F, et al. Crystal structure of the retinoblastoma protein N domain provides insight into tumor suppression, ligand interaction, and holoprotein architecture. Mol Cell. 2007;28:371–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Riley DJ, Liu CY, Lee WH. Mutations of N-terminal regions render the retinoblastoma protein insufficient for functions in development and tumor suppression. Mol Cell Biol. 1997;17:7342–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Otterson GA, Chen W, Coxon AB, Khleif SN, Kaye FJ. Incomplete penetrance of familial retinoblastoma linked to germ-line mutations that result in partial loss of RB function. Proc Natl Acad Sci USA. 1997;94:12036–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Lefevre SH, Chauveinc L, Stoppa-Lyonnet D, Michon J, Lumbroso L, Berthet P, et al. A T to C mutation in the polypyrimidine tract of the exon 9 splicing site of the RB1 gene responsible for low penetrance hereditary retinoblastoma. J Med Genet. 2002;39:E21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Sterner JM, Murata Y, Kim HG, Kennett SB, Templeton DJ, Horowitz JM. Detection of a novel cell cycle-regulated kinase activity that associates with the amino terminus of the retinoblastoma protein in G2/M phases. J Biol Chem. 1995;270:9281–8.

    Article  CAS  PubMed  Google Scholar 

  194. Goodrich DW. How the other half lives, the amino-terminal domain of the retinoblastoma tumor suppressor protein. J Cell Physiol. 2003;197:169–80.

    Article  CAS  PubMed  Google Scholar 

  195. Barrientes S, Cooke C, Goodrich DW. Glutamic acid mutagenesis of retinoblastoma protein phosphorylation sites has diverse effects on function. Oncogene. 2000;19:562–70.

    Article  CAS  PubMed  Google Scholar 

  196. Wu JR, Gilbert DM. The replication origin decision point is a mitogen-independent, 2-aminopurine-sensitive, G1-phase event that precedes restriction point control. Mol Cell Biol. 1997;17:4312–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Avni D, Yang H, Martelli F, Hofmann F, ElShamy WM, Ganesan S, et al. Active localization of the retinoblastoma protein in chromatin and its response to S phase DNA damage. Mol Cell. 2003;12:735–46.

    Article  CAS  PubMed  Google Scholar 

  198. Stengel KR, Dean JL, Seeley SL, Mayhew CN, Knudsen ES. RB status governs differential sensitivity to cytotoxic and molecularly-targeted therapeutic agents. Cell Cycle. 2008;7:1095–103.

    Article  CAS  PubMed  Google Scholar 

  199. Knudsen KE, Booth D, Naderi S, Sever-Chroneos Z, Fribourg AF, Hunton IC, et al. RB-dependent S-phase response to DNA damage. Mol Cell Biol. 2000;20:7751–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Kunnev D, Rusiniak ME, Kudla A, Freeland A, Cady GK, Pruitt SC. DNA damage response and tumorigenesis in Mcm2-deficient mice. Oncogene. 2010;29:3630–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Pruitt SC, Bailey KJ, Freeland A. Reduced Mcm2 expression results in severe stem/progenitor cell deficiency and cancer. Stem Cells. 2007;25:3121–32.

    Article  CAS  PubMed  Google Scholar 

  202. Kawabata T, Luebben SW, Yamaguchi S, Ilves I, Matise I, Buske T, et al. Stalled fork rescue via dormant replication origins in unchallenged S phase promotes proper chromosome segregation and tumor suppression. Mol Cell. 2011;41:543–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Shima N, Alcaraz A, Liachko I, Buske TR, Andrews CA, Munroe RJ, et al. A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice. Nat Genet. 2007;39:93–98.

    Article  CAS  PubMed  Google Scholar 

  204. Nepon-Sixt BS, Bryant VL, Alexandrow MG. Myc-driven chromatin accessibility regulates Cdc45 assembly into CMG helicases. Commun Biol. 2019;2:110.

    Article  PubMed  PubMed Central  Google Scholar 

  205. Koch HB, Zhang R, Verdoodt B, Bailey A, Zhang CD, Yates JR III, et al. Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach. Cell Cycle. 2007;6:205–17.

    Article  CAS  PubMed  Google Scholar 

  206. Maya-Mendoza A, Ostrakova J, Kosar M, Hall A, Duskova P, Mistrik M, et al. Myc and Ras oncogenes engage different energy metabolism programs and evoke distinct patterns of oxidative and DNA replication stress. Mol Oncol. 2015;9:601–16.

    Article  CAS  PubMed  Google Scholar 

  207. Costantino L, Sotiriou SK, Rantala JK, Magin S, Mladenov E, Helleday T, et al. Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science. 2014;343:88–91.

    Article  CAS  PubMed  Google Scholar 

  208. Teixeira LK, Reed SI. Cyclin E deregulation and genomic instability. Adv Exp Med Biol. 2017;1042:527–47.

    Article  CAS  PubMed  Google Scholar 

  209. Macheret M, Halazonetis TD. Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress. Nature. 2018;555:112–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Das SP, Borrman T, Liu VW, Yang SC, Bechhoefer J, Rhind N. Replication timing is regulated by the number of MCMs loaded at origins. Genome Res. 2015;25:1886–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Gemble S, Wardenaar R, Keuper K, Srivastava N, Nano M, Mace AS, et al. Genetic instability from a single S phase after whole-genome duplication. Nature. 2022;604:146–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Seo YS, Kang YH. The human replicative helicase, the CMG complex, as a target for anti-cancer therapy. Front Mol Biosci. 2018;5:26.

    Article  PubMed  PubMed Central  Google Scholar 

  213. Lu HP, Du XF, Li JD, Huang SN, He RQ, Wu HY, et al. Expression of cell division cycle protein 45 in tissue microarrays and the CDC45 gene by bioinformatics analysis in human hepatocellular carcinoma and patient outcomes. Med Sci Monit. 2021;27:e928800.

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Tan DF, Huberman JA, Hyland A, Loewen GM, Brooks JS, Beck AF, et al. MCM2-a promising marker for premalignant lesions of the lung: a cohort study. BMC Cancer. 2001;1:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Ramnath N, Hernandez FJ, Tan DF, Huberman JA, Natarajan N, Beck AF, et al. MCM2 is an independent predictor of survival in patients with non-small-cell lung cancer. J Clin Oncol. 2001;19:4259–66.

    Article  CAS  PubMed  Google Scholar 

  216. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

    Article  PubMed  Google Scholar 

  217. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    Article  PubMed  PubMed Central  Google Scholar 

  218. Ren B, Yu G, Tseng GC, Cieply K, Gavel T, Nelson J, et al. MCM7 amplification and overexpression are associated with prostate cancer progression. Oncogene. 2006;25:1090–8.

    Article  CAS  PubMed  Google Scholar 

  219. Zhang R, Liu Z, Zhang G. CDC45 modulates MCM7 expression and inhibits cell proliferation by suppressing the PI3K/AKT pathway in acute myeloid leukemia. Am J Transl Res. 2021;13:10218–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Minella AC, Welcker M, Clurman BE. Ras activity regulates cyclin E degradation by the Fbw7 pathway. Proc Natl Acad Sci USA. 2005;102:9649–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Kapeli K, Hurlin PJ. Differential regulation of N-Myc and c-Myc synthesis, degradation, and transcriptional activity by the Ras/mitogen-activated protein kinase pathway. J Biol Chem. 2011;286:38498–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Tsai WB, Aiba I, Long Y, Lin HK, Feun L, Savaraj N, et al. Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells. Cancer Res. 2012;72:2622–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Leone G, DeGregori J, Sears R, Jakoi L, Nevins JR. Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature. 1997;387:422–6.

    Article  CAS  PubMed  Google Scholar 

  224. Sears R, Leone G, DeGregori J, Nevins JR. Ras enhances Myc protein stability. Mol Cell. 1999;3:169–79.

    Article  CAS  PubMed  Google Scholar 

  225. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 2000;14:2501–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Kruszewski W, Kowara R, Rzepko R, Warezak C, Zielinski J, Gryglewski G, et al. K-RAS point mutation, and amplification of C-MYC and C-ERBB2 in colon adenocarcinoma. Folia Histochem Cytobiol. 2004;42:173–9.

    CAS  PubMed  Google Scholar 

  227. Field JK, Spandidos DA. The role of ras and myc oncogenes in human solid tumours and their relevance in diagnosis and prognosis (review). Anticancer Res. 1990;10:1–22.

    CAS  PubMed  Google Scholar 

  228. Bochman ML, Bell SP, 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.

  229. Schwacha A, Bell SP. Interactions between two catalytically distinct MCM subgroups are essential for coordinated ATP hydrolysis and DNA replication. Mol Cell. 2001;8:1093–104.

    Article  CAS  PubMed  Google Scholar 

  230. Wang D, Alvarez-Cabrera AL, Chen XS. Study of SV40 large T antigen nucleotide specificity for DNA unwinding. Virol J. 2017;14:79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Ma X, Liu Y, Liu Y, Alexandrov LB, Edmonson MN, Gawad C, et al. Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours. Nature. 2018;555:371–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Chen X, Bahrami A, Pappo A, Easton J, Dalton J, Hedlund E, et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 2014;7:104–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. OR E, Dhami SPS, Baev DV, Ortutay C, Halpin-McCormick A, Morrell R, et al. Repression of Mcl-1 expression by the CDC7/CDK9 inhibitor PHA-767491 overcomes bone marrow stroma-mediated drug resistance in AML. Sci Rep. 2018;8:15752.

    Article  PubMed Central  Google Scholar 

  234. Gad SA, Ali HEA, Gaballa R, Abdelsalam RM, Zerfaoui M, Ali HI, et al. Targeting CDC7 sensitizes resistance melanoma cells to BRAF(V600E)-specific inhibitor by blocking the CDC7/MCM2-7 pathway. Sci Rep. 2019;9:14197.

    Article  PubMed  PubMed Central  Google Scholar 

  235. Iwai K, Nambu T, Dairiki R, Ohori M, Yu J, Burke K, et al. Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor. Sci Adv. 2019;5:eaav3660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Cheng AN, Lo YK, Lin YS, Tang TK, Hsu CH, Hsu JT, et al. Identification of novel Cdc7 kinase inhibitors as anti-cancer agents that target the interaction with Dbf4 by the fragment complementation and drug repositioning approach. EBioMedicine. 2018;36:241–51.

    Article  PubMed  PubMed Central  Google Scholar 

  237. McLaughlin RP, He J, van der Noord VE, Redel J, Foekens JA, Martens JWM, et al. A kinase inhibitor screen identifies a dual cdc7/CDK9 inhibitor to sensitise triple-negative breast cancer to EGFR-targeted therapy. Breast Cancer Res. 2019;21:77.

    Article  PubMed  PubMed Central  Google Scholar 

  238. Menichincheri M, Albanese C, Alli C, Ballinari D, Bargiotti A, Caldarelli M, et al. Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding. J Med Chem. 2010;53:7296–315.

    Article  CAS  PubMed  Google Scholar 

  239. Masai H, Arai K. Cdc7 kinase complex: a key regulator in the initiation of DNA replication. J Cell Physiol. 2002;190:287–96.

    Article  CAS  PubMed  Google Scholar 

  240. Bousset K, Diffley JFX. The Cdc7 protein kinase is required for origin firing during S phase. Genes Dev. 1998;12:480–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Pasero P, Duncker BP, Schwob E, Gasser SM. A role for the Cdc7 kinase regulatory subunit Dbf4p in the formation of initiation-competent origins of replication. Genes Dev. 1999;13:2159–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Labib K. How do Cdc7 and cyclin-dependent kinases trigger the initiation of chromosome replication in eukaryotic cells? Genes Dev (Rev). 2010;24:1208–19.

    Article  CAS  Google Scholar 

  243. Long DT, Joukov V, Budzowska M, Walter JC. BRCA1 promotes unloading of the CMG helicase from a stalled DNA replication fork. Mol Cell. 2014;56:174–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Merajver SD, Pham TM, Caduff RF, Chen M, Poy EL, Cooney KA, et al. Somatic mutations in the BRCA1 gene in sporadic ovarian tumours. Nat Genet. 1995;9:439–43.

    Article  CAS  PubMed  Google Scholar 

  245. Mori T, Aoki T, Matsubara T, Iida F, Du X, Nishihira T, et al. Frequent loss of heterozygosity in the region including BRCA1 on chromosome 17q in squamous cell carcinomas of the esophagus. Cancer Res. 1994;54:1638–40.

    CAS  PubMed  Google Scholar 

  246. Steele CD, Abbasi A, Islam SMA, Bowes AL, Khandekar A, Haase K, et al. Signatures of copy number alterations in human cancer. Nature. 2022;606:984–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Drews RM, Hernando B, Tarabichi M, Haase K, Lesluyes T, Smith PS, et al. A pan-cancer compendium of chromosomal instability. Nature. 2022;606:976–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Tamberg N, Tahk S, Koit S, Kristjuhan K, Kasvandik S, Kristjuhan A, et al. Keap1-MCM3 interaction is a potential coordinator of molecular machineries of antioxidant response and genomic DNA replication in metazoa. Sci Rep. 2018;8:12136.

    Article  PubMed  PubMed Central  Google Scholar 

  249. Mulvaney KM, Matson JP, Siesser PF, Tamir TY, Goldfarb D, Jacobs TM, et al. Identification and characterization of MCM3 as a Kelch-like ECH-associated Protein 1 (KEAP1) substrate. J Biol Chem. 2016;291:23719–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Emerson DJ, Zhao PA, Cook AL, Barnett RJ, Klein KN, Saulebekova D, et al. Cohesin-mediated loop anchors confine the locations of human replication origins. Nature. 2022;606:812–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Dequeker BJH, Scherr MJ, Brandao HB, Gassler J, Powell S, Gaspar I, et al. MCM complexes are barriers that restrict cohesin-mediated loop extrusion. Nature. 2022;606:197–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Ivanov MP, Ladurner R, Poser I, Beveridge R, Rampler E, Hudecz O, et al. The replicative helicase MCM recruits cohesin acetyltransferase ESCO2 to mediate centromeric sister chromatid cohesion. EMBO J. 2018;37:e97150.

  253. Takahashi TS, Basu A, Bermudez V, Hurwitz J, Walter JC. Cdc7-Drf1 kinase links chromosome cohesion to the initiation of DNA replication in Xenopus egg extracts. Genes Dev. 2008;22:1894–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Takahashi TS, Yiu P, Chou MF, Gygi S, Walter JC. Recruitment of Xenopus Scc2 and cohesin to chromatin requires the pre-replication complex. Nat Cell Biol. 2004;6:991–6.

    Article  CAS  PubMed  Google Scholar 

  255. Bloom MS, Koshland D, Guacci V. Cohesin function in cohesion, condensation, and DNA repair is regulated by Wpl1p via a common mechanism in Saccharomyces cerevisiae. Genetics. 2018;208:111–24.

    Article  CAS  PubMed  Google Scholar 

  256. Heidinger-Pauli JM, Mert O, Davenport C, Guacci V, Koshland D. Systematic reduction of cohesin differentially affects chromosome segregation, condensation, and DNA repair. Curr Biol. 2010;20:957–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Guacci V, Koshland D, Strunnikov A. A direct link between sister chromatid cohesion and chromosome condensation revealed through the analysis of MCD1 in S. cerevisiae. Cell. 1997;91:47–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Knockleby J, Lee H. Same partners, different dance: involvement of DNA replication proteins in centrosome regulation. Cell Cycle. 2010;9:4487–91.

    Article  CAS  PubMed  Google Scholar 

  259. Prasanth SG, Prasanth KV, Siddiqui K, Spector DL, Stillman B. Human Orc2 localizes to centrosomes, centromeres and heterochromatin during chromosome inheritance. EMBO J. 2004;23:2651–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Pediatric Cancer Foundation (nationalpcf.org; DRR) and research support to MGA from the National Institutes of Health (R01 GM140140-01) and the Adolescent and Young Adult Program at the Moffitt Cancer Center and Research Institute.

Author information

Authors and Affiliations

  1. Cancer Biology and Evolution Program, Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA

    Shengyan Xiang, Damon R. Reed & Mark G. Alexandrow

  2. Molecular Oncology Department, Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA

    Shengyan Xiang & Mark G. Alexandrow

  3. Department of Individualized Cancer Management, Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA

    Damon R. Reed

Authors
  1. Shengyan Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Damon R. Reed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark G. Alexandrow
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Composed and edited manuscript: SX. Designed figures, composed, and edited manuscript: DRR and MGA.

Corresponding authors

Correspondence to Damon R. Reed or Mark G. Alexandrow.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiang, S., Reed, D.R. & Alexandrow, M.G. The CMG helicase and cancer: a tumor “engine” and weakness with missing mutations. Oncogene 42, 473–490 (2023). https://doi.org/10.1038/s41388-022-02572-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02572-8

This article is cited by

Search

Advanced search

Quick links