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

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Abstract

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.

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References

  • 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):6396–6406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Christiano C, Chini S, Chen J (2003) Human claspin is required for replication checkpoint control. J Biol Chem 278:30057–30062

    Article  Google Scholar 

  • 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):1391–1397

    Article  PubMed  Google Scholar 

  • Deegan TD, Yeeles JT, Diffley JF (2016) Phosphopeptide binding by Sld3 links Dbf4-dependent kinase to MCM replicative helicase activation. EMBO J 35(9):961–973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Errico A, Costanzo V (2012) Mechanisms of replication fork protection: a safeguard or genome stability. Crit Rev Biochem Mol Biol 47(3):222–235

    Article  CAS  PubMed  Google Scholar 

  • Gadaleta MC, Medina AG, Noguchi E (2016) Timeless protection of telomeres. Curr Genet 62:725–730. doi:10.1007/s00294-016-0599-x

    Article  CAS  PubMed  Google Scholar 

  • 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):358–366

    Article  CAS  PubMed  Google Scholar 

  • Gispan A, Carmi M, Barkai N (2014) Checkpoint-independent scaling of the Saccharomyces cerevisiae DNA replication program. BMC Biol 12:79

    Article  PubMed  PubMed Central  Google Scholar 

  • Hae YY, Jeong SY, Dunphy WG (2006) Site-specific phosphorylation of a checkpoint mediator protein controls its responses to different DNA structures. Genes Dev 20:772–783

    Article  Google Scholar 

  • 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 31:2380–2391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 26:137–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JM et al (2008) Cdc7 kinase mediates Claspin phosphorylation in DNA replication checkpoint. Oncogene 27:3475–3482

    Article  CAS  PubMed  Google Scholar 

  • 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):5008–5019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koren A, Soifer I, Barkai N (2010) MRC1-dependent scaling of the budding yeast DNA replication timing program. Genome Res 20:781–790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 6:839–849

    Article  CAS  PubMed  Google Scholar 

  • Kumagai A, Dunphy WG (2003) Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1. Nat Cell Biol 5:161–165

    Article  CAS  PubMed  Google Scholar 

  • 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):5269–5282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 11:329–340

    Article  CAS  PubMed  Google Scholar 

  • 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 101:6484–6489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 284:33107–33114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu T et al (2014) A divergent role of the SIRT1-TopBP1 axis in regulating metabolic checkpoint and DNA damage checkpoint. Mol Cell 56:681–695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Masai H, Arai K-I (2002) Cdc7 kinase complex: a key regulator in the initiation of DNA replication. J Cell Physiol 190(3):287–296

    Article  CAS  PubMed  Google Scholar 

  • Masai H, Matsumoto S, You Z, Yoshizawa-Sugata N, Oda M (2010) Eukaryotic chromosome DNA replication: where, when, and how? Annu Rev Biochem 79:89–130

    Article  CAS  PubMed  Google Scholar 

  • 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):4627–4637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 195:387–401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 

  • Muñoz S, Méndez J (2016) DNA replication stress: from molecular mechanisms to human disease. Chromosoma. doi:10.1007/s00412-016-0573-x

    PubMed  Google Scholar 

  • Murakami H, Keeney S (2014) Temporaspatial coordination of meiotic DNA replication and recombination via DDK recruitment to replisomes. Cell 158:861–873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  PubMed Central  Google Scholar 

  • 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 12:1560–1568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):39289–39295

    Article  CAS  PubMed  Google Scholar 

  • Sheu YJ, Stillman B (2006) Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression. Mol Cell 24:101–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 14:669–682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szyjka SJ, Viggiani CJ, Aparicio OM (2005) Mrc1 is required for normal progression of replication forks throughout chromatin in S. cerevisiae. Mol Cell 19:691–697

    Article  CAS  PubMed  Google Scholar 

  • 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 290:19923–19932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanaka K, Russell P (2001) Mrc1 channels the DNA replication arrest signal to checkpoint kinase Cds1. Nat Cell Biol 3(11):966–972

    Article  CAS  PubMed  Google Scholar 

  • Xu YJ, Davenport M, Kelly TJ (2006) Two-stage mechanism for activation of the DNA replication checkpoint kinase Cds1 in fission yeast. Genes Dev 20:990–1003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 7:12135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yeeles JT, Janska A, Early A, Diffley JF (2017) How the eukaryotic replisome achieves rapid and efficient DNA replication. Mol Cell 65(1):105–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):8395–8403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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

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Correspondence to Hisao Masai.

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Communicated by M. Kupiec.

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Masai, H., Yang, CC. & Matsumoto, S. Mrc1/Claspin: a new role for regulation of origin firing. Curr Genet 63, 813–818 (2017). https://doi.org/10.1007/s00294-017-0690-y

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  • DOI: https://doi.org/10.1007/s00294-017-0690-y

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