The Cdk8/19-cyclin C Transcription Regulator Functions in Genome Replication Through Metazoan Sld7

Overview

Journal PLoS Biol

Specialty Biology

Date 2019 Jan 30

PMID 30695077

Citations 20

Authors

Kerstin Kohler

Luis Sanchez-Pulido

Verena Hofer

Anika Marko

Chris P Ponting

Ambrosius P Snijders

Regina Feederle

Aloys Schepers

Dominik Boos

Affiliations

Soon will be listed here.

Abstract

Accurate genome duplication underlies genetic homeostasis. Metazoan Mdm2 binding protein (MTBP) forms a main regulatory platform for origin firing together with Treslin/TICRR and TopBP1 (Topoisomerase II binding protein 1 (TopBP1)-interacting replication stimulating protein/TopBP1-interacting checkpoint and replication regulator). We report the first comprehensive analysis of MTBP and reveal conserved and metazoa-specific MTBP functions in replication. This suggests that metazoa have evolved specific molecular mechanisms to adapt replication principles conserved with yeast to the specific requirements of the more complex metazoan cells. We uncover one such metazoa-specific process: a new replication factor, cyclin-dependent kinase 8/19-cyclinC (Cdk8/19-cyclin C), binds to a central domain of MTBP. This interaction is required for complete genome duplication in human cells. In the absence of MTBP binding to Cdk8/19-cyclin C, cells enter mitosis with incompletely duplicated chromosomes, and subsequent chromosome segregation occurs inaccurately. Using remote homology searches, we identified MTBP as the metazoan orthologue of yeast synthetic lethal with Dpb11 7 (Sld7). This homology finally demonstrates that the set of yeast core factors sufficient for replication initiation in vitro is conserved in metazoa. MTBP and Sld7 contain two homologous domains that are present in no other protein, one each in the N and C termini. In MTBP the conserved termini flank the metazoa-specific Cdk8/19-cyclin C binding region and are required for normal origin firing in human cells. The N termini of MTBP and Sld7 share an essential origin firing function, the interaction with Treslin/TICRR or its yeast orthologue Sld3, respectively. The C termini may function as homodimerisation domains. Our characterisation of broadly conserved and metazoa-specific initiation processes sets the basis for further mechanistic dissection of replication initiation in vertebrates. It is a first step in understanding the distinctions of origin firing in higher eukaryotes.

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References

Sanchez-Pulido L, Diffley J, Ponting C . Homology explains the functional similarities of Treslin/Ticrr and Sld3. Curr Biol. 2010; 20(12):R509-10. DOI: 10.1016/j.cub.2010.05.021. View

Jones D . Protein secondary structure prediction based on position-specific scoring matrices. J Mol Biol. 1999; 292(2):195-202. DOI: 10.1006/jmbi.1999.3091. View

Soding J, Biegert A, Lupas A . The HHpred interactive server for protein homology detection and structure prediction. Nucleic Acids Res. 2005; 33(Web Server issue):W244-8. PMC: 1160169. DOI: 10.1093/nar/gki408. View

Boos D, Sanchez-Pulido L, Rappas M, Pearl L, Oliver A, Ponting C . Regulation of DNA replication through Sld3-Dpb11 interaction is conserved from yeast to humans. Curr Biol. 2011; 21(13):1152-7. DOI: 10.1016/j.cub.2011.05.057. View

Wu C, Apweiler R, Bairoch A, Natale D, Barker W, Boeckmann B . The Universal Protein Resource (UniProt): an expanding universe of protein information. Nucleic Acids Res. 2005; 34(Database issue):D187-91. PMC: 1347523. DOI: 10.1093/nar/gkj161. View

Tanaka T, Umemori T, Endo S, Muramatsu S, Kanemaki M, Kamimura Y . Sld7, an Sld3-associated protein required for efficient chromosomal DNA replication in budding yeast. EMBO J. 2011; 30(10):2019-30. PMC: 3098486. DOI: 10.1038/emboj.2011.115. View

Ge X, Jackson D, Blow J . Dormant origins licensed by excess Mcm2-7 are required for human cells to survive replicative stress. Genes Dev. 2007; 21(24):3331-41. PMC: 2113033. DOI: 10.1101/gad.457807. View

Carrera I, Janody F, Leeds N, Duveau F, Treisman J . Pygopus activates Wingless target gene transcription through the mediator complex subunits Med12 and Med13. Proc Natl Acad Sci U S A. 2008; 105(18):6644-9. PMC: 2373359. DOI: 10.1073/pnas.0709749105. View

Sansam C, Pietrzak K, Majchrzycka B, Kerlin M, Chen J, Rankin S . A mechanism for epigenetic control of DNA replication. Genes Dev. 2018; 32(3-4):224-229. PMC: 5859964. DOI: 10.1101/gad.306464.117. View

10.

Guo C, Kumagai A, Schlacher K, Shevchenko A, Shevchenko A, Dunphy W . Interaction of Chk1 with Treslin negatively regulates the initiation of chromosomal DNA replication. Mol Cell. 2015; 57(3):492-505. PMC: 4321788. DOI: 10.1016/j.molcel.2014.12.003. View

11.

Bell S, Dutta A . DNA replication in eukaryotic cells. Annu Rev Biochem. 2002; 71:333-74. DOI: 10.1146/annurev.biochem.71.110601.135425. View

12.

Zegerman P, Diffley J . Phosphorylation of Sld2 and Sld3 by cyclin-dependent kinases promotes DNA replication in budding yeast. Nature. 2006; 445(7125):281-5. DOI: 10.1038/nature05432. View

13.

van Deursen F, Sengupta S, Piccoli G, Sanchez-Diaz A, Labib K . Mcm10 associates with the loaded DNA helicase at replication origins and defines a novel step in its activation. EMBO J. 2012; 31(9):2195-206. PMC: 3343467. DOI: 10.1038/emboj.2012.69. View

14.

Kohler G, Milstein C . Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975; 256(5517):495-7. DOI: 10.1038/256495a0. View

15.

Masumoto H, Muramatsu S, Kamimura Y, Araki H . S-Cdk-dependent phosphorylation of Sld2 essential for chromosomal DNA replication in budding yeast. Nature. 2002; 415(6872):651-5. DOI: 10.1038/nature713. View

16.

Evrin C, Clarke P, Zech J, Lurz R, Sun J, Uhle S . 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(48):20240-5. PMC: 2787165. DOI: 10.1073/pnas.0911500106. View

17.

Wohlschlegel J, Dhar S, Prokhorova T, Dutta A, Walter J . Xenopus Mcm10 binds to origins of DNA replication after Mcm2-7 and stimulates origin binding of Cdc45. Mol Cell. 2002; 9(2):233-40. DOI: 10.1016/s1097-2765(02)00456-2. View

18.

Hashimoto Y, Takisawa H . Xenopus Cut5 is essential for a CDK-dependent process in the initiation of DNA replication. EMBO J. 2003; 22(10):2526-35. PMC: 155996. DOI: 10.1093/emboj/cdg238. View

19.

Tanaka S, Umemori T, Hirai K, Muramatsu S, Kamimura Y, Araki H . CDK-dependent phosphorylation of Sld2 and Sld3 initiates DNA replication in budding yeast. Nature. 2006; 445(7125):328-32. DOI: 10.1038/nature05465. View

20.

Yeeles J, Janska A, Early A, Diffley J . How the Eukaryotic Replisome Achieves Rapid and Efficient DNA Replication. Mol Cell. 2016; 65(1):105-116. PMC: 5222725. DOI: 10.1016/j.molcel.2016.11.017. View