| Structural highlights
Function
[DBF4_YEAST] Regulatory subunit of the CDC7-DBF4 kinase, also called DBF4-dependent kinase (DDK), which is involved in cell cycle regulation of premitotic and premeiotic chromosome replication and in chromosome segregation. DDK plays an essential role in initiating DNA replication at replication origins by phosphorylating the MCM2 and MCM4 subunits of the MCM2-7 helicase complex. DBF4 recruits the catalytic subunit CDC7 to MCM2 and to origins of replication. DDK has also postreplicative functions in meiosis. DDK phosphorylates the meiosis-specific double-strand break protein MER2 for initiation of meiotic recombination. Interacts with CDC5 during meiosis to promote double-strand breaks and monopolar spindle orientation. Inhibits CDC5 activity during mitosis through direct binding to its PBD.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
Dbf4 is a conserved eukaryotic protein that functions as the regulatory subunit of the DDK (Dbf4-dependent kinase) complex. DDK plays essential roles in DNA replication initiation and checkpoint activation. During the replication checkpoint, Saccharomyces cerevisiae Dbf4 is phosphorylated in a Rad53-dependent manner and this, in turn, inhibits initiation of replication at late origins. We have determined the minimal region of Dbf4 required for the interaction with the checkpoint kinase Rad53 and solved its crystal structure. The core of this fragment of Dbf4 folds as a BRCT domain, but it includes an additional N-terminal helix unique to Dbf4. Mutation of the residues that anchor this helix to the domain core abolish the interaction between Dbf4 and Rad53, indicating that this helix is an integral element of the domain. The structure also reveals that previously characterized Dbf4 mutants with checkpoint phenotypes destabilize the domain, indicating that its structural integrity is essential for the interaction with Rad53. Collectively, these results allow us to propose a model for the association between Dbf4 and Rad53.
Saccharomyces cerevisiae DBF4 reveals a unique fold necessary for the interaction with the RAD53 kinase.,Matthews LA, Jones DR, Prasad AA, Duncker BP, Guarne A J Biol Chem. 2011 Nov 29. PMID:22130670[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dowell SJ, Romanowski P, Diffley JF. Interaction of Dbf4, the Cdc7 protein kinase regulatory subunit, with yeast replication origins in vivo. Science. 1994 Aug 26;265(5176):1243-6. PMID:8066465
- ↑ Duncker BP, Shimada K, Tsai-Pflugfelder M, Pasero P, Gasser SM. An N-terminal domain of Dbf4p mediates interaction with both origin recognition complex (ORC) and Rad53p and can deregulate late origin firing. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16087-92. Epub 2002 Nov 19. PMID:12441400 doi:https://dx.doi.org/10.1073/pnas.252093999
- ↑ Valentin G, Schwob E, Della Seta F. Dual role of the Cdc7-regulatory protein Dbf4 during yeast meiosis. J Biol Chem. 2006 Feb 3;281(5):2828-34. Epub 2005 Nov 30. PMID:16319063 doi:https://dx.doi.org/10.1074/jbc.M510626200
- ↑ Sheu YJ, Stillman B. Cdc7-Dbf4 phosphorylates MCM proteins via a docking site-mediated mechanism to promote S phase progression. Mol Cell. 2006 Oct 6;24(1):101-13. PMID:17018296 doi:https://dx.doi.org/10.1016/j.molcel.2006.07.033
- ↑ Matos J, Lipp JJ, Bogdanova A, Guillot S, Okaz E, Junqueira M, Shevchenko A, Zachariae W. Dbf4-dependent CDC7 kinase links DNA replication to the segregation of homologous chromosomes in meiosis I. Cell. 2008 Nov 14;135(4):662-78. doi: 10.1016/j.cell.2008.10.026. PMID:19013276 doi:https://dx.doi.org/10.1016/j.cell.2008.10.026
- ↑ Wan L, Niu H, Futcher B, Zhang C, Shokat KM, Boulton SJ, Hollingsworth NM. Cdc28-Clb5 (CDK-S) and Cdc7-Dbf4 (DDK) collaborate to initiate meiotic recombination in yeast. Genes Dev. 2008 Feb 1;22(3):386-97. doi: 10.1101/gad.1626408. PMID:18245450 doi:https://dx.doi.org/10.1101/gad.1626408
- ↑ Bruck I, Kaplan D. Dbf4-Cdc7 phosphorylation of Mcm2 is required for cell growth. J Biol Chem. 2009 Oct 16;284(42):28823-31. doi: 10.1074/jbc.M109.039123. Epub, 2009 Aug 18. PMID:19692334 doi:https://dx.doi.org/10.1074/jbc.M109.039123
- ↑ Miller CT, Gabrielse C, Chen YC, Weinreich M. Cdc7p-Dbf4p regulates mitotic exit by inhibiting Polo kinase. PLoS Genet. 2009 May;5(5):e1000498. doi: 10.1371/journal.pgen.1000498. Epub 2009 , May 29. PMID:19478884 doi:https://dx.doi.org/10.1371/journal.pgen.1000498
- ↑ Jones DR, Prasad AA, Chan PK, Duncker BP. The Dbf4 motif C zinc finger promotes DNA replication and mediates resistance to genotoxic stress. Cell Cycle. 2010 May 15;9(10):2018-26. Epub 2010 May 15. PMID:20436286
- ↑ Chen YC, Weinreich M. Dbf4 regulates the Cdc5 Polo-like kinase through a distinct non-canonical binding interaction. J Biol Chem. 2010 Dec 31;285(53):41244-54. doi: 10.1074/jbc.M110.155242. Epub, 2010 Oct 29. PMID:21036905 doi:https://dx.doi.org/10.1074/jbc.M110.155242
- ↑ Kaplan DL, Bruck I. Methods to study kinase regulation of the replication fork helicase. Methods. 2010 Jul;51(3):358-62. doi: 10.1016/j.ymeth.2010.02.013. Epub 2010 Feb, 17. PMID:20170732 doi:https://dx.doi.org/10.1016/j.ymeth.2010.02.013
- ↑ Sheu YJ, Stillman B. The Dbf4-Cdc7 kinase promotes S phase by alleviating an inhibitory activity in Mcm4. Nature. 2010 Jan 7;463(7277):113-7. doi: 10.1038/nature08647. PMID:20054399 doi:https://dx.doi.org/10.1038/nature08647
- ↑ Matthews LA, Jones DR, Prasad AA, Duncker BP, Guarne A. Saccharomyces cerevisiae DBF4 reveals a unique fold necessary for the interaction with the RAD53 kinase. J Biol Chem. 2011 Nov 29. PMID:22130670 doi:10.1074/jbc.M111.233973
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