Skip to main content

Meier-Gorlin Syndrome

  • 1326 Accesses

Abstract

Proteins required for the earliest stages of the initiation of DNA replication, including the origin recognition complex, Cdc6, Cdt1, and the Mcm2-7 proteins, cooperate to assemble pre-replicative complexes at all origins of DNA replication prior to the actual start of DNA synthesis from each origin during S phase of the cell division cycle. These initiation proteins are also involved in processes at centrosomes and centromeres during mitosis that ensure the correct segregation of the duplicated sister chromatids after DNA replication. Rare, recessive mutations in genes encoding some of these proteins result in Meier-Gorlin syndrome (MGS), characterized by microcephaly and primordial dwarfism, but normal intelligence. Biochemical and cell biology studies show that MGS mutations affect DNA replication, but some mutations affect both DNA replication and chromosome segregation. The observations have implications related to control of tissue and body size.

Keywords

  • Origin recognition complex
  • Cdc6
  • Cdt1
  • Centriole
  • Mitosis
  • Centrosome

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

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-319-24696-3_25
  • Chapter length: 22 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   189.00
Price excludes VAT (USA)
  • ISBN: 978-3-319-24696-3
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   249.99
Price excludes VAT (USA)
Hardcover Book
USD   249.99
Price excludes VAT (USA)
Fig. 25.1
Fig. 25.2
Fig. 25.3
Fig. 25.4

References

  1. Brown P, Sutikna T, Morwood MJ, Soejono RP, et al. A new small-bodied hominin from the Late Pleistocene of Flores, Indonesia. Nature. 2004;431:1055–61. doi:10.1038/nature02999.

    PubMed  CAS  CrossRef  Google Scholar 

  2. An P. An early Minoan microcephale. Anthropos. 1975;2:40–7.

    Google Scholar 

  3. Henneberg M, Thorne A. Flores human may be pathological Homo sapiens. Before Farming. 2004;4:2–4.

    Google Scholar 

  4. Vannucci RC, Barron TF, Holloway RL. Craniometric ratios of microcephaly and LB1, Homo floresiensis, using MRI and endocasts. Proc Natl Acad Sci U S A. 2011;108:14043–8. doi:10.1073/pnas.1105585108.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  5. Siklar Z, Berberoglu M. Syndromic disorders with short stature. J Clin Res Pediatr Endocrinol. 2014;6:1–8. doi:10.4274/Jcrpe.1149.

    PubMed Central  PubMed  CrossRef  Google Scholar 

  6. Meier Z, Poschiavo, Rothschild M. [Case of arthrogryposis multiplex congenita with mandibulofacial dysostosis (Franceschetti syndrome)]. Helv Paediatr Acta. 1959;14:213–6.

    PubMed  Google Scholar 

  7. Gorlin RJ, Cervenka J, Moller K, Horrobin M, Witkop Jr CJ. Malformation syndromes. A selected miscellany. Birth Defects Orig Artic Ser. 1975;11:39–50.

    PubMed  CAS  Google Scholar 

  8. Cohen B, Temple IK, Symons JC, Hall CM, Shaw DG, Bhamra M, et al. Microtia and short stature: a new syndrome. J Med Genet. 1991;28:786–90.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  9. Hurst JA, Winter RM, Baraitser M. Distinctive syndrome of short stature, craniosynostosis, skeletal changes, and malformed ears. Am J Med Genet. 1988;29:107–15. doi:10.1002/ajmg.1320290113.

    PubMed  CAS  CrossRef  Google Scholar 

  10. Boles RG, Teebi AS, Schwartz D, Harper JF. Further delineation of the ear, patella, short stature syndrome (Meier-Gorlin syndrome). Clin Dysmorphol. 1994;3:207–14.

    PubMed  CAS  Google Scholar 

  11. Buebel MS, Salinas CF, Pai GS, Macpherson RI, Greer MK, PerezComas A. A new Seckel-like syndrome of primordial dwarfism. Am J Med Genet. 1996;64:447–52.

    PubMed  CAS  CrossRef  Google Scholar 

  12. Lacombe D, Toutain A, Gorlin RJ, Oley CA, Battin J. Clinical identification of a human equivalent to the short ear (se) murine phenotype. Ann Genet. 1994;37:184–91.

    PubMed  CAS  Google Scholar 

  13. Fryns JP. Meier-Gorlin syndrome: the adult phenotype. Clin Dysmorphol. 1998;7:231–2.

    PubMed  CAS  CrossRef  Google Scholar 

  14. Loeys BL, Lemmerling MM, Van Mol CE, Leroy JG. The Meier-Gorlin syndrome, or ear patella short stature syndrome, in sibs. Am J Med Genet. 1999;84:61–7. doi:10.1002/(Sici)1096-8628(19990507)84:1<61::Aid-Ajmg12>3.0.Co;2-6.

    PubMed  CAS  CrossRef  Google Scholar 

  15. Teebi AS, Gorlin RJ. Not a new Seckel-like syndrome but ear-patella short stature syndrome. Am J Med Genet. 1997;70:454. doi:10.1002/(Sici)1096-8628(19970627)70:4<454::Aid-Ajmg23>3.0.Co;2-F.

    PubMed  CAS  CrossRef  Google Scholar 

  16. Verhallen JTCM vdLN, Kant SG. Het syndroom van Meier-Gorlin. Tijdschr Kindergeneesk 1999;67:32–5.

    Google Scholar 

  17. Bongers EMHF, Opitz JM, Fryer A, Sarda P, Hennekam RCM, Hall BD, et al. Meier-Gorlin syndrome: report of eight additional cases and review. Am J Med Genet. 2001;102:115–24. doi:10.1002/Ajmg.1452.

    PubMed  CAS  CrossRef  Google Scholar 

  18. Cohen A, Mulas R, Seri M, Gaiero A, Fichera G, Marini M, et al. Meier-Gorlin syndrome (ear-patella-short stature syndrome) in an Italian patient: Clinical evaluation and analysis of possible candidate genes. Am J Med Genet. 2002;107:48–51. doi:10.1002/Ajmg.10083.

    PubMed  CrossRef  Google Scholar 

  19. Bicknell LS, Bongers EM, Leitch A, Brown S, Schoots J, Harley ME, et al. Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nat Genet. 2011;43:356–9. doi:10.1038/ng.775.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  20. Bicknell LS, Walker S, Klingseisen A, Stiff T, Leitch A, Kerzendorfer C, et al. Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nat Genet. 2011;43:350–5. doi:10.1038/ng.776.

    PubMed  CAS  CrossRef  Google Scholar 

  21. de Munnik SA, Bicknell LS, Aftimos S, Al-Aama JY, van Bever Y, Bober MB, et al. Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis. Eur J Hum Genet. 2012;20:598–606. doi:10.1038/Ejhg.2011.269.

    PubMed Central  PubMed  CrossRef  CAS  Google Scholar 

  22. Guernsey DL, Matsuoka M, Jiang H, Evans S, Macgillivray C, Nightingale M, et al. Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome. Nat Genet. 2011;43:360–4. doi:10.1038/ng.777.

    PubMed  CAS  CrossRef  Google Scholar 

  23. Majewski F, Goecke T. Studies of micro-cephalic primordial dwarfism. 1. Approach to a delineation of the Seckel syndrome. Am J Med Genet. 1982;12:7–21. doi:10.1002/Ajmg.1320120103.

    PubMed  CAS  CrossRef  Google Scholar 

  24. Seckel HPG. Bird-headed dwarfs: studies in developmental anthropology including human proportions. Springfield, IL: Charles C. Thomas; 1960.

    Google Scholar 

  25. Hall JG, Flora C, Scott CI, Pauli RM, Tanaka KI. Majewski osteodysplastic primordial dwarfism type II (MOPD II): natural history and clinical findings. Am J Med Genet A. 2004;130A:55–72. doi:10.1002/Ajmg.A.30203.

    PubMed  CrossRef  Google Scholar 

  26. Majewski F, Ranke M, Schinzel A. Studies of micro-cephalic primordial dwarfism. 2. The osteodysplastic type-II of primordial dwarfism. Am J Med Genet. 1982;12:23–35. doi:10.1002/Ajmg.1320120104.

    PubMed  CAS  CrossRef  Google Scholar 

  27. O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet. 2003;33:497–501. doi:10.1038/ng1129.

    PubMed  CrossRef  CAS  Google Scholar 

  28. Al-Dosari MS, Shaheen R, Colak D, Alkuraya FS. Novel CENPJ mutation causes Seckel syndrome. J Med Genet. 2010;47:411–4. doi:10.1136/jmg.2009.076646.

    PubMed  CAS  CrossRef  Google Scholar 

  29. McIntyre RE, Lakshminarasimhan Chavali P, Ismail O, Carragher DM, Sanchez-Andrade G, Forment JV, et al. Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome. PLoS Genet. 2012;8, e1003022. doi:10.1371/journal.pgen.1003022.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  30. Kalay E, Yigit G, Aslan Y, Brown KE, Pohl E, Bicknell LS, et al. CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet. 2011;43:23–6. doi:10.1038/Ng.725.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  31. Qvist P, Huertas P, Jimeno S, Nyegaard M, Hassan MJ, Jackson SP, et al. CtIP mutations cause Seckel and Jawad syndromes. PLoS Genet. 2011;7, e1002310. doi:10.1371/journal.pgen.1002310.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  32. Nagy R, Wang H, Albrecht B, Wieczorek D, Gillessen-Kaesbach G, Haan E, et al. Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the RNU4ATAC gene. Clin Genet. 2012;82:140–6. doi:10.1111/j.1399-0004.2011.01756.x.

    PubMed  CAS  CrossRef  Google Scholar 

  33. Griffith E, Walker S, Martin CA, Vagnarelli P, Stiff T, Vernay B, et al. Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat Genet. 2008;40:232–6. doi:10.1038/ng.2007.80.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  34. Rauch A, Thiel CT, Schindler D, Wick U, Crow YJ, Ekici AB, et al. Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science. 2008;319:816–9. doi:10.1126/science.1151174.

    PubMed  CAS  CrossRef  Google Scholar 

  35. de Munnik SA, Otten BJ, Schoots J, Bicknell LS, Aftimos S, Al-Aama JY, et al. Meier-Gorlin syndrome: growth and secondary sexual development of a microcephalic primordial dwarfism disorder. Am J Med Genet A. 2012;158A:2733–42. doi:10.1002/ajmg.a.35681.

    PubMed  CrossRef  CAS  Google Scholar 

  36. Shalev SA, Khayat M, Etty DS, Elpeleg O. Further insight into the phenotype associated with a mutation in the ORC6 gene, causing Meier-Gorlin syndrome 3. Am J Med Genet A. 2015;167A:607–11. doi:10.1002/ajmg.a.36906.

    PubMed  CrossRef  CAS  Google Scholar 

  37. Bleichert F, Balasov M, Chesnokov I, Nogales E, Botchan MR, Berger JM. A Meier-Gorlin syndrome mutation in a conserved C-terminal helix of Orc6 impedes origin recognition complex formation. eLife. 2013;2, e00882. doi:10.7554/eLife.00882.

    PubMed Central  PubMed  CrossRef  CAS  Google Scholar 

  38. Hossain M, Stillman B. Meier-Gorlin syndrome mutations disrupt an Orc1 CDK inhibitory domain and cause centrosome reduplication. Genes Dev. 2012;26:1797–810. doi:10.1101/gad.197178.112.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  39. Stiff T, Alagoz M, Alcantara D, Outwin E, Brunner HG, Bongers EM, et al. Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of Meier-Gorlin syndrome. PLoS Genet. 2013;9, e1003360. doi:10.1371/journal.pgen.1003360.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  40. Chistol G, Walter JC. Single-molecule visualization of MCM2-7 DNA loading: seeing is believing. Cell. 2015;161:429–30. doi:10.1016/j.cell.2015.04.006.

    PubMed  CAS  CrossRef  Google Scholar 

  41. Diffley JF. Regulation of early events in chromosome replication. Curr Biol. 2004;14:R778–86. doi:10.1016/j.cub.2004.09.019.

    PubMed  CAS  CrossRef  Google Scholar 

  42. Diffley JF. Quality control in the initiation of eukaryotic DNA replication. Philos Trans R Soc Lond B Biol Sci. 2011;366:3545–53. doi:10.1098/rstb.2011.0073.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  43. Gerbi SA, Strezoska Z, Waggener JM. Initiation of DNA replication in multicellular eukaryotes. J Struct Biol. 2002;140:17–30.

    PubMed  CAS  CrossRef  Google Scholar 

  44. Lei M, Tye BK. Initiating DNA synthesis: from recruiting to activating the MCM complex. J Cell Sci. 2001;114:1447–54.

    PubMed  CAS  Google Scholar 

  45. Riera A, Tognetti S, Speck C. Helicase loading: how to build a MCM2-7 double-hexamer. Semin Cell Dev Biol. 2014;30:104–9. doi:10.1016/j.semcdb.2014.03.008.

    PubMed  CAS  CrossRef  Google Scholar 

  46. Sclafani RA, Holzen TM. Cell cycle regulation of DNA replication. Annu Rev Genet. 2007;41:237–80. doi:10.1146/annurev.genet.41.110306.130308.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  47. Stillman B. Cell cycle control of DNA replication. Science. 1996;274:1659–64.

    PubMed  CAS  CrossRef  Google Scholar 

  48. Bell SP, Stillman B. ATP-dependent recognition of eukaryotic origins of DNA replication by a multiprotein complex. Nature. 1992;357:128–34. doi:10.1038/357128a0.

    PubMed  CAS  CrossRef  Google Scholar 

  49. Bell SP. The origin recognition complex: from simple origins to complex functions. Genes Dev. 2002;16:659–72. doi:10.1101/gad.969602.

    PubMed  CAS  CrossRef  Google Scholar 

  50. Aves SJ, Liu Y, Richards TA. Evolutionary diversification of eukaryotic DNA replication machinery. Subcell Biochem. 2012;62:19–35. doi:10.1007/978-94-007-4572-8_2.

    PubMed  CAS  CrossRef  Google Scholar 

  51. Duncker BP, Chesnokov IN, McConkey BJ. The origin recognition complex protein family. Genome Biol. 2009;10:214. doi:10.1186/gb-2009-10-3-214.

    PubMed Central  PubMed  CrossRef  CAS  Google Scholar 

  52. Samson RY, Xu Y, Gadelha C, Stone TA, Faqiri JN, Li D, et al. Specificity and function of archaeal DNA replication initiator proteins. Cell Rep. 2013;3:485–96. doi:10.1016/j.celrep.2013.01.002.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  53. Iyer LM, Leipe DD, Koonin EV, Aravind L. Evolutionary history and higher order classification of AAA+ ATPases. J Struct Biol. 2004;146:11–31. doi:10.1016/j.jsb.2003.10.010.

    PubMed  CAS  CrossRef  Google Scholar 

  54. Speck C, Chen Z, Li H, Stillman B. ATPase-dependent cooperative binding of ORC and Cdc6 to origin DNA. Nat Struct Mol Biol. 2005;12:965–71. doi:10.1038/nsmb1002.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  55. DePamphilis ML. Cell cycle dependent regulation of the origin recognition complex. Cell Cycle. 2005;4:70–9.

    PubMed  CAS  CrossRef  Google Scholar 

  56. Kara N, Hossain M, Prasanth SG, Stillman B. Orc1 binding to mitotic chromosomes precedes spatial patterning during G1 phase and assembly of the origin recognition complex in human cells. J Biol Chem. 2015. doi:10.1074/jbc.M114.625012.

    PubMed Central  Google Scholar 

  57. Kreitz S, Ritzi M, Baack M, Knippers R. The human origin recognition complex protein 1 dissociates from chromatin during S phase in HeLa cells. J Biol Chem. 2001;276:6337–42. doi:10.1074/jbc.M009473200.

    PubMed  CAS  CrossRef  Google Scholar 

  58. McNairn AJ, Okuno Y, Misteli T, Gilbert DM. Chinese hamster ORC subunits dynamically associate with chromatin throughout the cell-cycle. Exp Cell Res. 2005;308:345–56. doi:10.1016/j.yexcr.2005.05.009.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  59. Mendez J, Zou-Yang XH, Kim SY, Hidaka M, Tansey WP, Stillman B. Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication. Mol Cell. 2002;9:481–91.

    PubMed  CAS  CrossRef  Google Scholar 

  60. Siddiqui K, Stillman B. ATP-dependent assembly of the human origin recognition complex. J Biol Chem. 2007;282:32370–83. doi:10.1074/jbc.M705905200.

    PubMed  CAS  CrossRef  Google Scholar 

  61. Okuno Y, McNairn AJ, den Elzen N, Pines J, Gilbert DM. Stability, chromatin association and functional activity of mammalian pre-replication complex proteins during the cell cycle. EMBO J. 2001;20:4263–77. doi:10.1093/emboj/20.15.4263.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  62. Tatsumi Y, Ohta S, Kimura H, Tsurimoto T, Obuse C. The ORC1 cycle in human cells: I. cell cycle-regulated oscillation of human ORC1. J Biol Chem. 2003;278:41528–34. doi:10.1074/jbc.M307534200.

    PubMed  CAS  CrossRef  Google Scholar 

  63. Bell SP, Kaguni JM. Helicase loading at chromosomal origins of replication. Cold Spring Harb Perspect Biol. 2013;5:a010124. doi:10.1101/cshperspect.a010124.

    PubMed Central  PubMed  Google Scholar 

  64. Donaldson AD, Blow JJ. The regulation of replication origin activation. Curr Opin Genet Dev. 1999;9:62–8.

    PubMed  CAS  CrossRef  Google Scholar 

  65. Renard-Guillet C, Kanoh Y, Shirahige K, Masai H. Temporal and spatial regulation of eukaryotic DNA replication: from regulated initiation to genome-scale timing program. Semin Cell Dev Biol. 2014;30:110–20. doi:10.1016/j.semcdb.2014.04.014.

    PubMed  CAS  CrossRef  Google Scholar 

  66. 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.

    PubMed  CAS  CrossRef  Google Scholar 

  67. Loo S, Fox CA, 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 Central  PubMed  CAS  CrossRef  Google Scholar 

  68. Hickman MA, Rusche LN. Transcriptional silencing functions of the yeast protein Orc1/Sir3 subfunctionalized after gene duplication. Proc Natl Acad Sci U S A. 2010;107:19384–9. doi:10.1073/pnas.1006436107.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  69. Abdurashidova G, Danailov MB, Ochem A, Triolo G, Djeliova V, Radulescu S, et al. Localization of proteins bound to a replication origin of human DNA along the cell cycle. EMBO J. 2003;22:4294–303. doi:10.1093/emboj/cdg404.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  70. Giordano-Coltart J, Ying CY, Gautier J, Hurwitz J. Studies of the properties of human origin recognition complex and its Walker A motif mutants. Proc Natl Acad Sci U S A. 2005;102:69–74. doi:10.1073/pnas.0408690102.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  71. Grallert B, Nurse P. The ORC1 homolog orp1 in fission yeast plays a key role in regulating onset of S phase. Genes Dev. 1996;10:2644–54. doi:10.1101/Gad.10.20.2644.

    PubMed  CAS  CrossRef  Google Scholar 

  72. Kuo AJ, Song J, Cheung P, Ishibe-Murakami S, Yamazoe S, Chen JK, et al. The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome. Nature. 2012;484:115–9. doi:10.1038/nature10956.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  73. Ladenburger EM, Keller C, Knippers R. Identification of a binding region for human origin recognition complex proteins 1 and 2 that coincides with an origin of DNA replication. Mol Cell Biol. 2002;22:1036–48.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  74. Ohta S, Tatsumi Y, Fujita M, Tsurimoto T, Obuse C. The ORC1 cycle in human cells: II. Dynamic changes in the human ORC complex during the cell cycle. J Biol Chem. 2003;278:41535–40. doi:10.1074/jbc.M307535200.

    PubMed  CAS  CrossRef  Google Scholar 

  75. Romanowski P, Madine MA, Rowles A, Blow JJ, Laskey RA. The Xenopus origin recognition complex is essential for DNA replication and MCM binding to chromatin. Curr Biol. 1996;6:1416–25. doi:10.1016/S0960-9822(96)00746-4.

    PubMed  CAS  CrossRef  Google Scholar 

  76. Rowles A, Chong JPJ, Brown L, Howell M, Evan GI, Blow JJ. Interaction between the origin recognition complex and the replication licensing system in Xenopus. Cell. 1996;87:287–96. doi:10.1016/S0092-8674(00)81346-X.

    PubMed  CAS  CrossRef  Google Scholar 

  77. Vujcic M, Miller CA, Kowalski D. Activation of silent replication origins at autonomously replicating sequence elements near the HML locus in budding yeast. Mol Cell Biol. 1999;19:6098–109.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  78. Wu PY, Nurse P. Establishing the program of origin firing during S phase in fission yeast. Cell. 2009;136:852–64. doi:10.1016/j.cell.2009.01.017.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  79. Muzi-Falconi M, Kelly TJ. Orp1, a member of the Cdc18/Cdc6 family of S-phase regulators, is homologous to a component of the origin recognition complex. Proc Natl Acad Sci U S A. 1995;92:12475–9.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  80. 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. doi:10.1101/gad.1084203.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  81. Vashee S, Simancek P, Challberg MD, Kelly TJ. Assembly of the human origin recognition complex. J Biol Chem. 2001;276:26666–73. doi:10.1074/jbc.M102493200.

    PubMed  CAS  CrossRef  Google Scholar 

  82. Wu M, Lu W, Santos RE, Frattini MG, Kelly TJ. Geminin inhibits a late step in the formation of human pre-replicative complexes. J Biol Chem. 2014;289:30810–21. doi:10.1074/jbc.M114.552935.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  83. Prasanth SG, Shen Z, Prasanth KV, Stillman B. Human origin recognition complex is essential for HP1 binding to chromatin and heterochromatin organization. Proc Natl Acad Sci U S A. 2010;107:15093–8. doi:10.1073/pnas.1009945107.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  84. Sasaki T, Gilbert DM. The many faces of the origin recognition complex. Curr Opin Cell Biol. 2007;19:337–43. doi:10.1016/j.ceb.2007.04.007.

    PubMed  CAS  CrossRef  Google Scholar 

  85. McNairn AJ, Gilbert DM. Overexpression of ORC subunits and increased ORC-chromatin association in transformed mammalian cells. J Cell Biochem. 2005;96:879–87. doi:10.1002/jcb.20609.

    PubMed  CAS  CrossRef  Google Scholar 

  86. Hemerly AS, Prasanth SG, Siddiqui K, Stillman B. Orc1 controls centriole and centrosome copy number in human cells. Science. 2009;323:789–93. doi:10.1126/science.1166745.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  87. Beck DB, Burton A, Oda H, Ziegler-Birling C, Torres-Padilla ME, Reinberg D. The role of PR-Set7 in replication licensing depends on Suv4-20 h. Genes Dev. 2012;26:2580–9. doi:10.1101/gad.195636.112.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  88. Burke TW, Cook JG, Asano M, Nevins JR. Replication factors MCM2 and ORC1 interact with the histone acetyltransferase HBO1. J Biol Chem. 2001;276:15397–408. doi:10.1074/jbc.M011556200.

    PubMed  CAS  CrossRef  Google Scholar 

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

    PubMed  CAS  CrossRef  Google Scholar 

  90. Mendoza-Maldonado R, Paolinelli R, Galbiati L, Giadrossi S, Giacca M. Interaction of the retinoblastoma protein with Orc1 and its recruitment to human origins of DNA replication. PLoS One. 2010;5, e13720. doi:10.1371/journal.pone.0013720.

    PubMed Central  PubMed  CrossRef  CAS  Google Scholar 

  91. Auth T, Kunkel E, Grummt F. Interaction between HP1alpha and replication proteins in mammalian cells. Exp Cell Res. 2006;312:3349–59. doi:10.1016/j.yexcr.2006.07.014.

    PubMed  CAS  CrossRef  Google Scholar 

  92. Lidonnici MR, Rossi R, Paixao S, Mendoza-Maldonado R, Paolinelli R, Arcangeli C, et al. Subnuclear distribution of the largest subunit of the human origin recognition complex during the cell cycle. J Cell Sci. 2004;117:5221–31. doi:10.1242/jcs.01405.

    PubMed  CAS  CrossRef  Google Scholar 

  93. Bartke T, Vermeulen M, Xhemalce B, Robson SC, Mann M, Kouzarides T. Nucleosome-interacting proteins regulated by DNA and histone methylation. Cell. 2010;143:470–84. doi:10.1016/j.cell.2010.10.012.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  94. Giri S, Aggarwal V, Pontis J, Shen Z, Chakraborty A, Khan A, et al. The preRC protein ORCA organizes heterochromatin by assembling histone H3 lysine 9 methyltransferases on chromatin. eLife. 2015;4:PMCID:PMC4442312. doi:10.7554/eLife.06496.

    CrossRef  Google Scholar 

  95. Shen Z, Chakraborty A, Jain A, Giri S, Ha T, Prasanth KV, et al. Dynamic association of ORCA with prereplicative complex components regulates DNA replication initiation. Mol Cell Biol. 2012;32:3107–20. doi:10.1128/MCB.00362-12.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  96. Shen Z, Sathyan KM, Geng Y, Zheng R, Chakraborty A, Freeman B, et al. A WD-repeat protein stabilizes ORC binding to chromatin. Mol Cell. 2010;40:99–111. doi:10.1016/j.molcel.2010.09.021.

    PubMed  CAS  CrossRef  Google Scholar 

  97. Bleichert F, Botchan MR, Berger JM. Crystal structure of the eukaryotic origin recognition complex. Nature. 2015;519:321–6. doi:10.1038/nature14239.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  98. Zhang W, Sankaran S, Gozani O, Song J. A Meier-Gorlin syndrome mutation impairs the ORC1-nucleosome association. ACS Chem Biol. 2015. doi:10.1021/cb5009684.

    Google Scholar 

  99. Noguchi K, Vassilev A, Ghosh S, Yates JL, DePamphilis ML. The BAH domain facilitates the ability of human Orc1 protein to activate replication origins in vivo. EMBO J. 2006;25:5372–82. doi:10.1038/sj.emboj.7601396.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  100. Quintana DG, Hou Z, Thome KC, Hendricks M, Saha P, Dutta A. Identification of HsORC4, a member of the human origin of replication recognition complex. J Biol Chem. 1997;272:28247–51.

    PubMed  CAS  CrossRef  Google Scholar 

  101. Tugal T, Zou-Yang XH, Gavin K, Pappin D, Canas B, Kobayashi R, et al. The Orc4p and Orc5p subunits of the Xenopus and human origin recognition complex are related to Orc1p and Cdc6p. J Biol Chem. 1998;273:32421–9. doi:10.1074/Jbc.273.49.32421.

    PubMed  CAS  CrossRef  Google Scholar 

  102. Chuang RY, Kelly TJ. The fission yeast homologue of Orc4p binds to replication origin DNA via multiple AT-hooks. Proc Natl Acad Sci U S A. 1999;96:2656–61.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  103. Lee JK, Moon KY, Jiang Y, Hurwitz J. The Schizosaccharomyces pombe origin recognition complex interacts with multiple AT-rich regions of the replication origin DNA by means of the AT-hook domains of the spOrc4 protein. Proc Natl Acad Sci U S A. 2001;98:13589–94. doi:10.1073/pnas.251530398.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  104. Kong D, DePamphilis ML. Site-specific DNA binding of the Schizosaccharomyces pombe origin recognition complex is determined by the Orc4 subunit. Mol Cell Biol. 2001;21:8095–103. doi:10.1128/MCB.21.23.8095-8103.2001.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  105. Kong D, DePamphilis ML. Site-specific ORC binding, pre-replication complex assembly and DNA synthesis at Schizosaccharomyces pombe replication origins. EMBO J. 2002;21:5567–76.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  106. Kusic J, Tomic B, Divac A, Kojic S. Human initiation protein Orc4 prefers triple stranded DNA. Mol Biol Rep. 2010;37:2317–22. doi:10.1007/s11033-009-9735-8.

    PubMed  CAS  CrossRef  Google Scholar 

  107. Stefanovic D, Kusic J, Divac A, Tomic B. Formation of noncanonical DNA structures mediated by human ORC4, a protein component of the origin recognition complex. Biochemistry. 2008;47:8760–7. doi:10.1021/bi800684f.

    PubMed  CAS  CrossRef  Google Scholar 

  108. Stefanovic D, Stanojcic S, Vindigni A, Ochem A, Falaschi A. In vitro protein-DNA interactions at the human lamin B2 replication origin. J Biol Chem. 2003;278:42737–43. doi:10.1074/jbc.M307058200.

    PubMed  CAS  CrossRef  Google Scholar 

  109. 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.

    PubMed  CAS  CrossRef  Google Scholar 

  110. Chesnokov I, Remus D, Botchan M. Functional analysis of mutant and wild-type Drosophila origin recognition complex. Proc Natl Acad Sci U S A. 2001;98:11997–2002. doi:10.1073/pnas.211342798.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  111. Bowers JL, Randell JC, Chen S, Bell SP. ATP hydrolysis by ORC catalyzes reiterative Mcm2-7 assembly at a defined origin of replication. Mol Cell. 2004;16:967–78. doi:10.1016/j.molcel.2004.11.038.

    PubMed  CAS  CrossRef  Google Scholar 

  112. Dhar SK, Dutta A. Identification and characterization of the human ORC6 homolog. J Biol Chem. 2000;275:34983–8. doi:10.1074/jbc.M006069200.

    PubMed  CAS  CrossRef  Google Scholar 

  113. Liu S, Balasov M, Wang H, Wu L, Chesnokov IN, Liu Y. Structural analysis of human Orc6 protein reveals a homology with transcription factor TFIIB. Proc Natl Acad Sci U S A. 2011;108:7373–8. doi:10.1073/pnas.1013676108.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  114. Li JJ, Herskowitz I. Isolation of ORC6, a component of the yeast origin recognition complex by a one-hybrid system. Science. 1993;262:1870–4.

    PubMed  CAS  CrossRef  Google Scholar 

  115. Chesnokov IN, Chesnokova ON, Botchan M. A cytokinetic function of Drosophila ORC6 protein resides in a domain distinct from its replication activity. Proc Natl Acad Sci U S A. 2003;100:9150–5. doi:10.1073/pnas.1633580100.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  116. Prasanth SG, Prasanth KV, Stillman B. Orc6 involved in DNA replication, chromosome segregation, and cytokinesis. Science. 2002;297:1026–31. doi:10.1126/science.1072802.

    PubMed  CAS  CrossRef  Google Scholar 

  117. Semple JW, Da-Silva LF, Jervis EJ, Ah-Kee J, Al-Attar H, Kummer L, et al. An essential role for Orc6 in DNA replication through maintenance of pre-replicative complexes. EMBO J. 2006;25:5150–8. doi:10.1038/sj.emboj.7601391.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  118. Chen S, de Vries MA, Bell SP. Orc6 is required for dynamic recruitment of Cdt1 during repeated Mcm2-7 loading. Genes Dev. 2007;21:2897–907. doi:10.1101/gad.1596807.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  119. Balasov M, Huijbregts RP, Chesnokov I. Role of the Orc6 protein in origin recognition complex-dependent DNA binding and replication in Drosophila melanogaster. Mol Cell Biol. 2007;27:3143–53. doi:10.1128/MCB.02382-06.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  120. Wilmes GM, Archambault V, Austin RJ, Jacobson MD, Bell SP, Cross FR. Interaction of the S-phase cyclin Clb5 with an “RXL” docking sequence in the initiator protein Orc6 provides an origin-localized replication control switch. Genes Dev. 2004;18:981–91. doi:10.1101/gad.1202304.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  121. Balasov M, Huijbregts RP, Chesnokov I. Functional analysis of an Orc6 mutant in Drosophila. Proc Natl Acad Sci U S A. 2009;106:10672–7. doi:10.1073/pnas.0902670106.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  122. Huijbregts RP, Svitin A, Stinnett MW, Renfrow MB, Chesnokov I. Drosophila Orc6 facilitates GTPase activity and filament formation of the septin complex. Mol Biol Cell. 2009;20:270–81. doi:10.1091/mbc.E08-07-0754.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  123. Patel S, Latterich M. The AAA team: related ATPases with diverse functions. Trends Cell Biol. 1998;8:65–71. doi:10.1016/S0962-8924(97)01212-9.

    PubMed  CAS  CrossRef  Google Scholar 

  124. Neuwald AF, Aravind L, Spouge JL, Koonin EV. AAA(+): a class of chaperone-like ATPases associated with the assembly, operation, and disassembly of protein complexes. Genome Res. 1999;9:27–43.

    PubMed  CAS  Google Scholar 

  125. 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.

    PubMed  CAS  CrossRef  Google Scholar 

  126. Leatherwood J, LopezGirona A, Russell P. Interaction of Cdc2 and Cdc18 with a fission yeast ORC2-like protein. Nature. 1996;379:360–3. doi:10.1038/379360a0.

    PubMed  CAS  CrossRef  Google Scholar 

  127. Coleman TR, Carpenter PB, Dunphy WG. The Xenopus Cdc6 protein is essential for the initiation of a single round of DNA replication in cell-free extracts. Cell. 1996;87:53–63. doi:10.1016/S0092-8674(00)81322-7.

    PubMed  CAS  CrossRef  Google Scholar 

  128. 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. doi:10.1073/pnas.0911500106.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  129. Frigola J, Remus D, Mehanna A, Diffley JF. ATPase-dependent quality control of DNA replication origin licensing. Nature. 2013;495:339–43. doi:10.1038/nature11920.

    PubMed  CAS  CrossRef  Google Scholar 

  130. Sun J, Fernandez-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. doi:10.1101/gad.242313.114.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  131. Sun J, Kawakami H, Zech J, Speck C, Stillman B, Li H. Cdc6-induced conformational changes in ORC bound to origin DNA revealed by cryo-electron microscopy. Structure. 2012;20:534–44. doi:10.1016/j.str.2012.01.011.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  132. 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. doi:10.1016/j.cell.2009.10.015.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  133. 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. doi:10.1016/S1097-2765(00)80110-0.

    PubMed  CAS  CrossRef  Google Scholar 

  134. Liang C, Stillman B. Persistent initiation of DNA replication and chromatin-bound MCM proteins during the cell cycle in cdc6 mutants. Genes Dev. 1997;11:3375–86. doi:10.1101/Gad.11.24.3375.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  135. Jallepalli PV, Brown GW, MuziFalconi M, Tien D, Kelly TJ. Regulation of the replication initiator protein p65(cdc18) by CDK phosphorylation. Genes Dev. 1997;11:2767–79. doi:10.1101/Gad.11.21.2767.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  136. Nishitani H, Nurse P. P65(Cdc18) plays a major role controlling the initiation of DNA-replication in fission yeast. Cell. 1995;83:397–405. doi:10.1016/0092-8674(95)90117-5.

    PubMed  CAS  CrossRef  Google Scholar 

  137. Tanaka TU, Knapp D, Nasmyth K. Loading of an Mcm protein onto DNA replication origins is regulated by Cdc6p and CDKs. Cell. 1997;90:649–60. doi:10.1016/S0092-8674(00)80526-7.

    PubMed  CAS  CrossRef  Google Scholar 

  138. Nguyen VQ, Co C, Li JJ. Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms. Nature. 2001;411:1068–73. doi:10.1038/35082600.

    PubMed  CAS  CrossRef  Google Scholar 

  139. Kim GS, Kang J, Bang SW, Hwang DS. Cdc6 localizes to S- and G2-phase centrosomes in a cell cycle-dependent manner. Biochem Biophys Res Commun. 2015;456:763–7. doi:10.1016/j.bbrc.2014.12.018.

    PubMed  CAS  CrossRef  Google Scholar 

  140. Nishitani H, Lygerou Z, Nishimoto T. Proteolysis of DNA replication licensing factor Cdt1 in S-phase is performed independently of Geminin through its N-terminal region. J Biol Chem. 2004;279:30807–16. doi:10.1074/Jbc.M312644200.

    PubMed  CAS  CrossRef  Google Scholar 

  141. Maiorano D, Rul W, Mechali M. Cell cycle regulation of the licensing activity of Cdt1 in Xenopus laevis. Exp Cell Res. 2004;295:138–49. doi:10.1016/J.Yexcr.2003.11.018.

    PubMed  CAS  CrossRef  Google Scholar 

  142. Tsuyama T, Tada S, Watanabe S, Seki M, Enomoto T. Licensing for DNA replication requires a strict sequential assembly of Cdc6 and Cdt1 onto chromatin in Xenopus egg extracts. Nucleic Acids Res. 2005;33:765–75. doi:10.1093/Nar/Gki226.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  143. Yanagi K, Mizuno T, You ZY, 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. doi:10.1074/Jbc.M206202200.

    PubMed  CAS  CrossRef  Google Scholar 

  144. Ferenbach A, Li A, Brito-Martins M, Blow JJ. Functional domains of the Xenopus replication licensing factor Cdt1. Nucleic Acids Res. 2005;33:316–24. doi:10.1093/Nar/Gki176.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  145. Tanaka S, Diffley JFX. Interdependent nuclear accumulation of budding yeast Cdt1 and Mcm2-7 during G1 phase. Nat Cell Biol. 2002;4:198–207. doi:10.1038/Ncb757.

    PubMed  CAS  CrossRef  Google Scholar 

  146. Cook JG, Chasse DAD, Nevins JR. The regulated association of Cdt1 with minichromosome maintenance proteins and Cdc6 in mammalian cells. J Biol Chem. 2004;279:9625–33. doi:10.1074/Jbc.M311933200.

    PubMed  CAS  CrossRef  Google Scholar 

  147. Mihaylov IS, Kondo T, Jones L, Ryzhikov S, Tanaka J, Zheng JY, et al. Control of DNA replication and chromosome ploidy by geminin and cyclin A. Mol Cell Biol. 2002;22:1868–80. doi:10.1128/Mcb.22.6.1868-1880.2002.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  148. Vaziri C, Saxena S, Jeon Y, Lee C, Murata K, Machida Y, et al. A p53-dependent checkpoint pathway prevents rereplication (vol 11, pg 997, 2003). Mol Cell. 2003;11:1415. doi:10.1016/S1097-2765(03)00202-8.

    CAS  CrossRef  Google Scholar 

  149. Zhong W, Feng H, Santiago FE, Kipreos ET. CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing. Nature. 2003;423:885–9. doi:10.1038/nature01747.

    PubMed  CAS  CrossRef  Google Scholar 

  150. Melixetian M, Ballabeni A, Masiero L, Gasparini P, Zamponi R, Bartek J, et al. Loss of Geminin induces rereplication in the presence of functional p53. J Cell Biol. 2004;165:473–82. doi:10.1083/Jcb.200403106.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  151. Liu EB, Li XH, Yan F, Zhao QP, Wu XH. Cyclin-dependent kinases phosphorylate human Cdt1 and induce its degradation. J Biol Chem. 2004;279:17283–8. doi:10.1074/Jbc.C300549200.

    PubMed  CAS  CrossRef  Google Scholar 

  152. McGarry TJ, Kirschner MW. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell. 1998;93:1043–53. doi:10.1016/S0092-8674(00)81209-X.

    PubMed  CAS  CrossRef  Google Scholar 

  153. Ballabeni A, Melixetian M, Zamponi R, Masiero L, Marinoni F, Helin K. Human Geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis. EMBO J. 2004;23:3122–32. doi:10.1038/Sj.Emboj.7600314.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  154. Arias EE, Walter JC. PCNA functions as a molecular platform to trigger Cdt1 destruction and prevent re-replication. Nat Cell Biol. 2006;8:84-U33. doi:10.1038/Ncb1346.

    CrossRef  CAS  Google Scholar 

  155. Senga T, Sivaprasad U, Zhu WG, Park JH, Arias EE, Walter JC, et al. PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination. J Biol Chem. 2006;281:6246–52. doi:10.1074/Jbc.M512705200.

    PubMed  CAS  CrossRef  Google Scholar 

  156. Sugimoto N, Tatsumi Y, Tsurumi T, Matsukage A, Kiyono T, Nishitani H, et al. Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding. J Biol Chem. 2004;279:19691–7. doi:10.1074/Jbc.M313175200.

    PubMed  CAS  CrossRef  Google Scholar 

  157. Saxena S, Yuan P, Dhar SK, Senga T, Takeda D, Robinson H, et al. A dimerized coiled-coil domain and an adjoining part of geminin interact with two sites on Cdt1 for replication inhibition. Mol Cell. 2004;15:245–58. doi:10.1016/J.Molcel.2004.06.045.

    PubMed  CAS  CrossRef  Google Scholar 

  158. Kondo T, Kobayashi M, Tanaka J, Yokoyama A, Suzuki S, Kato N, et al. Rapid degradation of Cdt1 upon UV-induced DNA damage is mediated by SCFSkp2 complex. J Biol Chem. 2004;279:27315–9. doi:10.1074/jbc.M314023200.

    PubMed  CAS  CrossRef  Google Scholar 

  159. Thomer M, May NR, Aggarwal BD, Kwok G, Calvi BR. Drosophila double-parked is sufficient to induce re-replication during development and is regulated by cyclin E/CDK2. Development. 2004;131:4807–18. doi:10.1242/dev.01348.

    PubMed  CAS  CrossRef  Google Scholar 

  160. Xouri G, Lygerou Z, Nishitani H, Pachnis V, Nurse P, Taraviras S. Cdt1 and geminin are down-regulated upon cell cycle exit and are over-expressed in cancer-derived cell lines. Eur J Biochem. 2004;271:3368–78. doi:10.1111/J.1432-1033.2004.04271.X.

    PubMed  CAS  CrossRef  Google Scholar 

  161. Takeda DY, Parvin JD, Dutta A. Degradation of Cdt1 during S phase is Skp2-independent and is required for efficient progression of mammalian cells through S phase. J Biol Chem. 2005;280:23416–23. doi:10.1074/jbc.M501208200.

    PubMed  CAS  CrossRef  Google Scholar 

  162. Jin JP, Arias EE, Chen J, Harper JW, Walter JC. A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell. 2006;23:709–21. doi:10.1016/J.Molcel.2006.08.010.

    PubMed  CAS  CrossRef  Google Scholar 

  163. Kim Y, Kipreos ET. Cdt1 degradation to prevent DNA re-replication: conserved and non-conserved pathways. Cell Div. 2007;2:18. doi:10.1186/1747-1028-2-18.

    PubMed Central  PubMed  CrossRef  CAS  Google Scholar 

  164. 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. doi:10.1074/jbc.M109.075333.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  165. Jackson AP, Laskey RA, Coleman N. Replication proteins and human disease. Cold Spring Harb Perspect Biol. 2014;6:pii:a013060. doi:10.1101/cshperspect.a013060.

    CrossRef  CAS  Google Scholar 

  166. Gineau L, Cognet C, Kara N, Lach FP, Dunne J, Veturi U, et al. Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J Clin Invest. 2012;122:821–32. doi:10.1172/JCI61014.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  167. Hughes CR, Guasti L, Meimaridou E, Chuang CH, Schimenti JC, King PJ, et al. MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest. 2012;122:814–20. doi:10.1172/JCI60224.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

  168. Casey JP, Nobbs M, McGettigan P, Lynch S, Ennis S. Recessive mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair. J Med Genet. 2012;49:242–5. doi:10.1136/jmedgenet-2012-100803.

    PubMed  CAS  CrossRef  Google Scholar 

  169. Bernal JA, Venkitaraman AR. A vertebrate N-end rule degron reveals that Orc6 is required in mitosis for daughter cell abscission. J Cell Biol. 2011;192:969–78. doi:10.1083/jcb.201008125.

    PubMed Central  PubMed  CAS  CrossRef  Google Scholar 

Download references

Acknowledgements

Research in the author’s laboratory is supported by grants from the National Institutes of Health, CA13106 and GM45436.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bruce Stillman .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Hossain, M., Stillman, B. (2016). Meier-Gorlin Syndrome. In: Kaplan, D. (eds) The Initiation of DNA Replication in Eukaryotes. Springer, Cham. https://doi.org/10.1007/978-3-319-24696-3_25

Download citation