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• W2067220372 abstract "In yeast, phosphorylation of the Sld3 protein by cyclin-dependent kinases is essential for replication initiation. In metazoans, three potential Sld3 counterparts have emerged. A new study suggests that one of these, Treslin/Ticrr, is the Sld3 ortholog. In yeast, phosphorylation of the Sld3 protein by cyclin-dependent kinases is essential for replication initiation. In metazoans, three potential Sld3 counterparts have emerged. A new study suggests that one of these, Treslin/Ticrr, is the Sld3 ortholog. In vertebrate cells, DNA replication initiates from thousands of sites called origins of replication, a process that requires a cyclin-dependent kinase (CDK) [1Bell S.P. Dutta A. DNA replication in eukaryotic cells.Annu. Rev. Biochem. 2002; 71: 333-374Crossref PubMed Scopus (1365) Google Scholar]. One of the holy grails in the replication field has been the identification of functionally relevant S phase CDK substrates. The recent demonstration that Sld2 and Sld3 are the only essential CDK targets for replication initiation in yeast was an important breakthrough [2Tanaka 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. 2007; 445: 328-332Crossref PubMed Scopus (337) Google Scholar, 3Zegerman P. Diffley J.F. Phosphorylation of Sld2 and Sld3 by cyclin-dependent kinases promotes DNA replication in budding yeast.Nature. 2007; 445: 281-285Crossref PubMed Scopus (361) Google Scholar]. However, metazoan Sld2 and Sld3, as well as metazoan S phase CDK targets, remained elusive. In the last year, three different proteins (DUE-B, Treslin/Ticrr, and GEMC1) were identified that appear to have similar functions to Sld3, and at least one of these (GEMC1) was found to be a bona fide CDK target [4Balestrini A. Cosentino C. Errico A. Garner E. Costanzo V. GEMC1 is a TopBP1-interacting protein required for chromosomal DNA replication.Nat. Cell Biol. 2010; 12: 484-491Crossref PubMed Scopus (78) Google Scholar, 5Chowdhury A. Liu G. Kemp M. Chen X. Katrangi N. Myers S. Ghosh M. Yao J. Gao Y. Bubulya P. et al.The DNA unwinding element binding protein DUE-B interacts with Cdc45 in preinitiation complex formation.Mol. Cell Biol. 2010; 30: 1495-1507Crossref PubMed Scopus (43) Google Scholar, 6Kumagai A. Shevchenko A. Dunphy W.G. Treslin collaborates with TopBP1 in triggering the initiation of DNA replication.Cell. 2010; 140: 349-359Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 7Sansam C.L. Cruz N.M. Danielian P.S. Amsterdam A. Lau M.L. Hopkins N. Lees J.A. A vertebrate gene, ticrr, is an essential checkpoint and replication regulator.Genes Dev. 2010; 24: 183-194Crossref PubMed Scopus (89) Google Scholar]. However, none of the three proteins was shown to contain significant sequence similarity to Sld3. In a new report in this issue of Current Biology, Sanchez-Pulido and colleagues [8Sanchez-Pulido L. Diffley J.F.X. Ponting C.P. Homology explains the functional similarities of Treslin/Ticrr and Sld3.Curr. Biol. 2010; 20: R509-R510Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar] now show that significant sequence homology does in fact exist between Treslin/Ticrr and Sld3, suggesting an orthologous evolutionary relationship between these two proteins. As discussed below, this observation raises interesting questions about the evolutionary and functional relationship of Treslin/Ticrr to DUE-B and GEMC1. In all eukaryotic cells, replication initiation can be separated into two distinct steps that occur in different phases of the cell cycle (Figure 1). In G1, the origin recognition complex (ORC) binds to DNA and cooperates with Cdt1 and Cdc6 to recruit the MCM2–7 helicase. In S phase, CDK and DDK (Dbf4-dependent kinase) cooperate with Sld2, Sld3, Dpb11 and several other factors to activate the MCM2–7 helicase. The mechanism of this activation process is currently mysterious, but it involves the recruitment of two helicase co-factors, Cdc45 and GINS, to the MCM2–7 complex to form the CMG holo-helicase complex. Once activated, CMG unwinds the origin in preparation for DNA synthesis. In budding yeast, CDK promotes the interaction between Dpb11, Sld2, and Sld3 [2Tanaka 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. 2007; 445: 328-332Crossref PubMed Scopus (337) Google Scholar, 3Zegerman P. Diffley J.F. Phosphorylation of Sld2 and Sld3 by cyclin-dependent kinases promotes DNA replication in budding yeast.Nature. 2007; 445: 281-285Crossref PubMed Scopus (361) Google Scholar]. Specifically, Sld2 and Sld3 are phosphorylated on multiple sites by CDK, and this modification promotes the binding of these proteins to caboxy- and amino-terminal pairs of BRCT repeats within Dpb11, respectively. Via an unknown mechanism, the complex of Dpb11, Sld2, and Sld3 helps facilitate the formation of the CMG helicase. How conserved are these events in higher eukaryotic cells? In metazoans, TopBP1 (also called CUT5 or MUS101) is an excellent candidate for the Dpb11 ortholog: like Dpb11, it contains multiple BRCT motifs, the first three of which are necessary and sufficient to support chromosomal DNA replication [9Hashimoto Y. Tsujimura T. Sugino A. Takisawa H. The phosphorylated C-terminal domain of Xenopus Cut5 directly mediates ATR-dependent activation of Chk1.Genes Cells. 2006; 11: 993-1007Crossref PubMed Scopus (55) Google Scholar, 10Yan S. Lindsay H.D. Michael W.M. Direct requirement for Xmus101 in ATR-mediated phosphorylation of Claspin bound Chk1 during checkpoint signaling.J. Cell Biol. 2006; 173: 181-186Crossref PubMed Scopus (47) Google Scholar]. Moreover, TopBP1 stimulates the same initiation step as Dpb11, the origin association of Cdc45 and GINS [11Van Hatten R.A. Tutter A.V. Holway A.H. Khederian A.M. Walter J.C. Michael W.M. The Xenopus Xmus101 protein is required for the recruitment of Cdc45 to origins of DNA replication.J. Cell Biol. 2002; 159: 541-547Crossref PubMed Scopus (103) Google Scholar]. Based on sequence similarity, RecQL4 is a possible vertebrate homolog of Sld2. However, unlike Sld2, RecQL4 appears to function after Cdc45 and GINS have been loaded onto replication origins [12Matsuno K. Kumano M. Kubota Y. Hashimoto Y. Takisawa H. The N-terminal noncatalytic region of Xenopus RecQ4 is required for chromatin binding of DNA polymerase alpha in the initiation of DNA replication.Mol. Cell Biol. 2006; 26: 4843-4852Crossref PubMed Scopus (137) Google Scholar, 13Sangrithi M.N. Bernal J.A. Madine M. Philpott A. Lee J. Dunphy W.G. Venkitaraman A.R. Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome.Cell. 2005; 121: 887-898Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar]. Therefore, the CMG assembly function of Sld2 may have been replaced by another protein in higher eukaryotes. Three proteins, DUE-B, Treslin/Ticrr, and GEMC1, have all been proposed as possible candidates for the vertebrate Sld3 ortholog. DUE-B (DNA Unwinding Element Binding), was isolated as a c-myc origin binding protein [5Chowdhury A. Liu G. Kemp M. Chen X. Katrangi N. Myers S. Ghosh M. Yao J. Gao Y. Bubulya P. et al.The DNA unwinding element binding protein DUE-B interacts with Cdc45 in preinitiation complex formation.Mol. Cell Biol. 2010; 30: 1495-1507Crossref PubMed Scopus (43) Google Scholar]. Treslin (TopBP1-interacting, replication-stimulating protein) was isolated as a TopBP1-binding protein from Xenopus egg extracts [6Kumagai A. Shevchenko A. Dunphy W.G. Treslin collaborates with TopBP1 in triggering the initiation of DNA replication.Cell. 2010; 140: 349-359Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar]. The same protein was also recovered in a screen for checkpoint deficiency in zebrafish and called Ticrr (TopBP1-interacting, check-point, and replication regulator) [7Sansam C.L. Cruz N.M. Danielian P.S. Amsterdam A. Lau M.L. Hopkins N. Lees J.A. A vertebrate gene, ticrr, is an essential checkpoint and replication regulator.Genes Dev. 2010; 24: 183-194Crossref PubMed Scopus (89) Google Scholar]. Finally, GEMC1 was identified due to its partial homology with the coiled-coil domain of the Cdt1-inhibitor Geminin. Notably, GEMC1 does not bind to Cdt1, nor does it inhibit DNA replication. DUE-B, Treslin/Ticrr, and GEMC1 have all been characterized in some detail in Xenopus egg extracts. Like Sld3, all three proteins can be found in a complex with TopBP1, and they all function specifically at the Cdc45 loading step. Like Sld3, the DUE-B, Treslin/Ticrr, and GEMC1 proteins have also been connected to CDK activity. Thus, Treslin/Ticrr contains 35 potential CDK phosphorylation sites, and its binding to TopBP1 is stimulated by Cdk2, analogous to the interaction of Sld3 with Dpb11. Interestingly, like Sld3 [14Kamimura Y. Tak Y.S. Sugino A. Araki H. Sld3, which interacts with Cdc45 (Sld4), functions for chromosomal DNA replication in Saccharomyces cerevisiae.EMBO J. 2001; 20: 2097-2107Crossref PubMed Scopus (180) Google Scholar], the binding of Treslin/Ticrr to pre-replication complexes itself is not CDK-dependent. So far, however, specific Cdk2 phosphorylation sites on Treslin/Ticrr have not been implicated in the protein's function. In the case of GEMC1, its interaction with TopBP1 is compromised when eight CDK sites on GEMC1 are mutated. Importantly, these sites are also essential for the function of GEMC1 in DNA replication. These results establish GEMC1 as the first bona fide CDK target for replication initiation in metazoans. Unlike Treslin/Ticrr, GEMC1 chromatin loading is MCM2–7-independent, but ORC- and TopBP1-dependent. Finally, the CDK-dependence of DUE-B binding to TopBP1 is not yet clear. However, DUE-B binds to chromatin dependent on the pre-replication complex and Cdk2 activity. In summary, the regulation of DUE-B, Treslin/Ticrr, and GEMC1 by CDK is still being elucidated and therefore does not point unambiguously to one of these proteins as the metazoan Sld3 ortholog. Importantly, no compelling sequence homology was initially reported between Sld3 and DUE-B, Treslin/Ticrr, or GEMC1 [4Balestrini A. Cosentino C. Errico A. Garner E. Costanzo V. GEMC1 is a TopBP1-interacting protein required for chromosomal DNA replication.Nat. Cell Biol. 2010; 12: 484-491Crossref PubMed Scopus (78) Google Scholar, 5Chowdhury A. Liu G. Kemp M. Chen X. Katrangi N. Myers S. Ghosh M. Yao J. Gao Y. Bubulya P. et al.The DNA unwinding element binding protein DUE-B interacts with Cdc45 in preinitiation complex formation.Mol. Cell Biol. 2010; 30: 1495-1507Crossref PubMed Scopus (43) Google Scholar, 6Kumagai A. Shevchenko A. Dunphy W.G. Treslin collaborates with TopBP1 in triggering the initiation of DNA replication.Cell. 2010; 140: 349-359Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 7Sansam C.L. Cruz N.M. Danielian P.S. Amsterdam A. Lau M.L. Hopkins N. Lees J.A. A vertebrate gene, ticrr, is an essential checkpoint and replication regulator.Genes Dev. 2010; 24: 183-194Crossref PubMed Scopus (89) Google Scholar], raising the question whether any of these proteins is a true Sld3 ortholog. However, Sanchez-Pulido et al. [8Sanchez-Pulido L. Diffley J.F.X. Ponting C.P. Homology explains the functional similarities of Treslin/Ticrr and Sld3.Curr. Biol. 2010; 20: R509-R510Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar] now show that Treslin/Ticrr does in fact contain a domain that shares significant sequence homology with Sld3. The authors first interrogated the protein databases with Treslin/Ticrr using the sequence comparison method HMMer2 and found distant plant homologs [15Eddy S.R. Hidden Markov models.Curr. Opin. Struct. Biol. 1996; 6: 361-365Crossref PubMed Scopus (789) Google Scholar]. They then generated a profile from the animal and plant Treslin/Ticrr proteins, and used this to search the database. This yielded significant similarity (E = 8.6 x 10-15) to the fungal Sld3 family profile. These observations indicate that Treslin/Ticrr and Sld3 descended from a common ancestor that existed before the divergence of the principal eukaryotic lineages. Importantly, several of the temperature-sensitive mutations in fungal Sld3 proteins map to residues that are common to all Treslin/Ticrr and Sld3 proteins, and one of these disrupts the interaction of Sld3 with Cdc45. Together with the CDK-independent Treslin/Ticrr chromatin loading, this sequence analysis points to Treslin/Ticrr as the strongest candidate for the metazoan Sld3 protein. If Treslin/Ticrr is the true Sld3 ortholog, what are the evolutionary origins and functions of DUE-B and GEMC1? One possibility is that the function of Sld3 in replication initiation was divided among several proteins, some of which are not related by sequence to Sld3. This would afford metazoan organisms more CDK targets in replication initiation, allowing for additional regulatory inputs into this crucial event. Another possibility is that DUE-B or GEMC1 performs Sld2's role in CMG assembly. In this regard it is interesting that the recruitment of DUE-B to pre-replication complexes is Cdk2-dependent [5Chowdhury A. Liu G. Kemp M. Chen X. Katrangi N. Myers S. Ghosh M. Yao J. Gao Y. Bubulya P. et al.The DNA unwinding element binding protein DUE-B interacts with Cdc45 in preinitiation complex formation.Mol. Cell Biol. 2010; 30: 1495-1507Crossref PubMed Scopus (43) Google Scholar], which also appears to be the case for Sld2 [16Muramatsu S. Hirai K. Tak Y.S. Kamimura Y. Araki H. CDK-dependent complex formation between replication proteins Dpb11, Sld2, Pol ɛ, and GINS in budding yeast.Genes Dev. 2010; 24: 602-612Crossref PubMed Scopus (174) Google Scholar]. Most likely, the assembly of the CMG complex requires a similar set of molecular events in all eukaryotes. Only once these steps have been elucidated will it be possible to understand how these tasks are divided among different proteins in any specific organism." @default.
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• W2067220372 title "DNA Replication: Metazoan Sld3 Steps Forward" @default.
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