Current Genetics

, Volume 63, Issue 5, pp 813–818 | Cite as

Mrc1/Claspin: a new role for regulation of origin firing



Mrc1 and its vertebrate homologue Claspin serve as a mediator for replication stress checkpoint signaling, receiving the signal from Mec1/Rad3/ATR sensor kinase and transmitting it to the effector Rad53/Cds1/Chk1 kinase. They are likely to be a part of the replisome and facilitate the S-phase progression by promoting replication fork progression. Recent reports on Mrc1/Claspin indicate their new role in regulating the replication initiation through interaction with Cdc7, a key conserved serine–threonine kinase that triggers firing at each replication origin. Mrc1/Claspin has a specific domain that specifically interacts with Cdc7, and this domain is involved also in intramolecular interaction with its N-terminal segment. Mechanisms for novel regulation of origin firing and its timing through recruitment of Cdc7 to Mrc1/Claspin will be discussed.


Mrc1 Claspin Cdc7 kinase Replication timing Origin firing Intramolecular interaction 



We would like to thank all the members of our laboratory and other collaborators for helpful discussion, support, and continuous excitement.


  1. Alvino GM, Collingwood D, Murphy JM, Delrow J, Brewer BJ, Raghuraman MK (2007) Replication in hydroxyurea: it’s a matter of time. Mol Cell Biol 27(18):6396–6406CrossRefPubMedPubMedCentralGoogle Scholar
  2. Christiano C, Chini S, Chen J (2003) Human claspin is required for replication checkpoint control. J Biol Chem 278:30057–30062CrossRefGoogle Scholar
  3. Crabbé L, Thomas A, Pantesco V, De Vos J, Pasero P, Lengronne A (2010) Analysis of replication profiles reveals key role of RFC-Ctf18 in yeast replication stress response. Nat Struct Mol Biol 17(11):1391–1397CrossRefPubMedGoogle Scholar
  4. Deegan TD, Yeeles JT, Diffley JF (2016) Phosphopeptide binding by Sld3 links Dbf4-dependent kinase to MCM replicative helicase activation. EMBO J 35(9):961–973CrossRefPubMedPubMedCentralGoogle Scholar
  5. Errico A, Costanzo V (2012) Mechanisms of replication fork protection: a safeguard or genome stability. Crit Rev Biochem Mol Biol 47(3):222–235CrossRefPubMedGoogle Scholar
  6. Gadaleta MC, Medina AG, Noguchi E (2016) Timeless protection of telomeres. Curr Genet 62:725–730. doi: 10.1007/s00294-016-0599-x CrossRefPubMedGoogle Scholar
  7. Gambus A, Jones RC, Sanchez-Diaz A, Kanemaki M, van Deursen F, Edmondson RD, Labib K (2006) GINS maintains association of Cdc45 with MCM in replisome progression complexes at eukaryotic DNA replication forks. Nat Cell Biol 8(4):358–366CrossRefPubMedGoogle Scholar
  8. Gispan A, Carmi M, Barkai N (2014) Checkpoint-independent scaling of the Saccharomyces cerevisiae DNA replication program. BMC Biol 12:79CrossRefPubMedPubMedCentralGoogle Scholar
  9. Hae YY, Jeong SY, Dunphy WG (2006) Site-specific phosphorylation of a checkpoint mediator protein controls its responses to different DNA structures. Genes Dev 20:772–783CrossRefGoogle Scholar
  10. Hayano M, Kanoh Y, Matsumoto S, Masai H (2011) Mrc1 marks early-firing origins and coordinates timing and efficiency of initiation in fission yeast. Mol Cell Biol 31:2380–2391CrossRefPubMedPubMedCentralGoogle Scholar
  11. Hayano M, Kanoh Y, Matsumoto S, Renard-Guillet C, Shirahige K, Masai H (2012) Rif1 is a global regulator of timing of replication origin firing in fission yeast. Genes Dev 26:137–150CrossRefPubMedPubMedCentralGoogle Scholar
  12. Kim JM et al (2008) Cdc7 kinase mediates Claspin phosphorylation in DNA replication checkpoint. Oncogene 27:3475–3482CrossRefPubMedGoogle Scholar
  13. Komata M, Bando M, Araki H, Shirahige K (2009) The direct binding of Mrc1, a checkpoint mediator, to Mcm6, a replication helicase, is essential for the replication checkpoint against methyl methanesulfonate-induced stress. Mol Cell Biol 29(18):5008–5019CrossRefPubMedPubMedCentralGoogle Scholar
  14. Koren A, Soifer I, Barkai N (2010) MRC1-dependent scaling of the budding yeast DNA replication timing program. Genome Res 20:781–790CrossRefPubMedPubMedCentralGoogle Scholar
  15. Kumagai A, Dunphy WG (2000) Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts. Mol Cell 6:839–849CrossRefPubMedGoogle Scholar
  16. Kumagai A, Dunphy WG (2003) Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1. Nat Cell Biol 5:161–165CrossRefPubMedGoogle Scholar
  17. Lee J, Gold DA, Schevchenko A, Schevchenko A, Dunphy WG (2005) Roles of replication fork-interacting and Chk1-activating domains from claspin in a DNA replication checkpoint response. Mol Biol Cell 16(11):5269–5282CrossRefPubMedPubMedCentralGoogle Scholar
  18. Lee J, Kumagai A, Dunphy WG (2003) Claspin, a Chk1-regulatory protein, monitors DNA replication on chromatin independently of RPA, ATR, and Rad17. Mol Cell 11:329–340CrossRefPubMedGoogle Scholar
  19. Lin S-Y, Li K, Stewart GS, Elledge SJ (2004) Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation. Proc Natl Acad Sci USA 101:6484–6489CrossRefPubMedPubMedCentralGoogle Scholar
  20. Lindsey-Boltz LA, Serçin Ö, Choi JH, Sancar A (2009) Reconstitution of human claspin-mediated phosphorylation of Chk1 by the ATR (Ataxia Telangiectasia-mutated and Rad3-related) checkpoint kinase. J Biol Chem 284:33107–33114CrossRefPubMedPubMedCentralGoogle Scholar
  21. Liu T et al (2014) A divergent role of the SIRT1-TopBP1 axis in regulating metabolic checkpoint and DNA damage checkpoint. Mol Cell 56:681–695CrossRefPubMedPubMedCentralGoogle Scholar
  22. Masai H, Arai K-I (2002) Cdc7 kinase complex: a key regulator in the initiation of DNA replication. J Cell Physiol 190(3):287–296CrossRefPubMedGoogle Scholar
  23. Masai H, Matsumoto S, You Z, Yoshizawa-Sugata N, Oda M (2010) Eukaryotic chromosome DNA replication: where, when, and how? Annu Rev Biochem 79:89–130CrossRefPubMedGoogle Scholar
  24. Matsumoto S, Shimmoto M, Kakusho N, Yokoyama M, Kanoh Y, Hayano M, Russell P, Masai H (2010) Hsk1 kinase and Cdc45 regulate replication stress-induced checkpoint responses in fission yeast. Cell Cycle 9(23):4627–4637CrossRefPubMedPubMedCentralGoogle Scholar
  25. Matsumoto S, Hayano M, Kanoh Y, Masai H (2011) Multiple pathways can bypass the essential role of fission yeast Hsk1 kinase in DNA replication initiation. J Cell Biol 195:387–401CrossRefPubMedPubMedCentralGoogle Scholar
  26. Matsumoto S, Kanoh Y, Shimmoto M, Hayano M, Ueda K, Fukatsu R, Kakusho N, Masai H (2017) Checkpoint-independent regulation of origin firing by Mrc1 through interaction with Hsk1 kinase. Mol Cell Biol. doi: 10.1128/MCB.00355-16 Google Scholar
  27. Muñoz S, Méndez J (2016) DNA replication stress: from molecular mechanisms to human disease. Chromosoma. doi: 10.1007/s00412-016-0573-x PubMedGoogle Scholar
  28. Murakami H, Keeney S (2014) Temporaspatial coordination of meiotic DNA replication and recombination via DDK recruitment to replisomes. Cell 158:861–873CrossRefPubMedPubMedCentralGoogle Scholar
  29. Palou R, Palou G, Quintana DG (2016) A role for the spindle assembly checkpoint in the DNA damage response. Curr Genet. doi: 10.1007/s00294-016-0634-y PubMedPubMedCentralGoogle Scholar
  30. Rainey MD, Harhen B, Wang GN, Murphy PV, Santocanale C (2013) Cdc7-dependent and -independent phosphorylation of Claspin in the induction of the DNA replication checkpoint. Cell Cycle 12:1560–1568CrossRefPubMedPubMedCentralGoogle Scholar
  31. Sar F, Lindsey-Boltz LA, Subramanian D, Croteau DL, Hutsell SQ, Griffith JD, Sancar A (2004) Human claspin is a ring-shaped DNA-binding protein with high affinity to branched DNA structures. J Biol Chem 279(38):39289–39295CrossRefPubMedGoogle Scholar
  32. Sheu YJ, Stillman B (2006) Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression. Mol Cell 24:101–113CrossRefPubMedPubMedCentralGoogle Scholar
  33. Shimmoto M et al (2009) Interactions between Swi1–Swi3, Mrc1 and S phase kinase, Hsk1 may regulate cellular responses to stalled replication forks in fission yeast. Genes Cells 14:669–682CrossRefPubMedPubMedCentralGoogle Scholar
  34. Szyjka SJ, Viggiani CJ, Aparicio OM (2005) Mrc1 is required for normal progression of replication forks throughout chromatin in S. cerevisiae. Mol Cell 19:691–697CrossRefPubMedGoogle Scholar
  35. Takeishi Y, Iwaya-Omi R, Ohashi E, Tsurimoto T (2015) Intramolecular binding of the Rad9 C terminus in the checkpoint clamp Rad9–Hus1–Rad1 is closely linked with its DNA binding. J Biol Chem 290:19923–19932CrossRefPubMedPubMedCentralGoogle Scholar
  36. Tanaka K, Russell P (2001) Mrc1 channels the DNA replication arrest signal to checkpoint kinase Cds1. Nat Cell Biol 3(11):966–972CrossRefPubMedGoogle Scholar
  37. Xu YJ, Davenport M, Kelly TJ (2006) Two-stage mechanism for activation of the DNA replication checkpoint kinase Cds1 in fission yeast. Genes Dev 20:990–1003CrossRefPubMedPubMedCentralGoogle Scholar
  38. Yang CC, Suzuki M, Yamakawa S, Uno S, Ishii A, Yamazaki S, Fukatsu R, Fujisawa R, Sakimura K, Tsurimoto T, Masai H (2016) Claspin recruits Cdc7 kinase for initiation of DNA replication in human cells. Nat Commun 7:12135CrossRefPubMedPubMedCentralGoogle Scholar
  39. Yeeles JT, Janska A, Early A, Diffley JF (2017) How the eukaryotic replisome achieves rapid and efficient DNA replication. Mol Cell 65(1):105–116CrossRefPubMedPubMedCentralGoogle Scholar
  40. Zhao H, Tanaka K, Noguchi E, Noguchi C, Russell P (2003) Replication checkpoint protein Mrc1 is regulated by Rad3 and Tel1 in fission yeast. Mol Cell Biol 23(22):8395–8403CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Department of Genome MedicineTokyo Metropolitan Institute of Medical ScienceTokyoJapan

Personalised recommendations