| Structural highlights
Disease
[CDT1_HUMAN] Defects in CDT1 are the cause of Meier-Gorlin syndrome type 4 (MGORS4) [MIM:613804]. MGORS4 is a syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal.[1] [2]
Function
[MCM6_HUMAN] Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity.[3] [CDT1_HUMAN] Cooperates with CDC6 to promote the loading of the mini-chromosome maintenance complex onto chromatin to form the pre-replication complex necessary to initiate DNA replication. Binds DNA in a sequence-, strand-, and conformation-independent manner. Potential oncogene.[4] [5] [6] [7] [UniProtKB:Q8R4E9]
Publication Abstract from PubMed
Initiation of DNA replication in eukaryotes is exquisitely regulated to ensure that DNA replication occurs exactly once in each cell division. A conserved and essential step for the initiation of eukaryotic DNA replication is the loading of the mini-chromosome maintenance 2-7 (MCM2-7) helicase onto chromatin at replication origins by Cdt1. To elucidate the molecular mechanism of this event, we determined the structure of the human Cdt1-Mcm6 binding domains, the Cdt1(410-440)/MCM6(708-821) complex by NMR. Our structural and site-directed mutagenesis studies showed that charge complementarity is a key determinant for the specific interaction between Cdt1 and Mcm2-7. When this interaction was interrupted by alanine substitutions of the conserved interacting residues, the corresponding yeast Cdt1 and Mcm6 mutants were defective in DNA replication and the chromatin loading of Mcm2, resulting in cell death. Having shown that Cdt1 and Mcm6 interact through their C-termini, and knowing that Cdt1 is tethered to Orc6 during the loading of MCM2-7, our results suggest that the MCM2-7 hexamer is loaded with its C terminal end facing the ORC complex. These results provide a structural basis for the Cdt1-mediated MCM2-7 chromatin loading.
Structural insights into the Cdt1-mediated MCM2-7 chromatin loading.,Liu C, Wu R, Zhou B, Wang J, Wei Z, Tye BK, Liang C, Zhu G Nucleic Acids Res. 2012 Apr;40(7):3208-17. doi: 10.1093/nar/gkr1118. Epub 2011, Dec 2. PMID:22140117[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bicknell LS, Bongers EM, Leitch A, Brown S, Schoots J, Harley ME, Aftimos S, Al-Aama JY, Bober M, Brown PA, van Bokhoven H, Dean J, Edrees AY, Feingold M, Fryer A, Hoefsloot LH, Kau N, Knoers NV, Mackenzie J, Opitz JM, Sarda P, Ross A, Temple IK, Toutain A, Wise CA, Wright M, Jackson AP. Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nat Genet. 2011 Feb 27;43(4):356-9. doi: 10.1038/ng.775. PMID:21358632 doi:10.1038/ng.775
- ↑ Guernsey DL, Matsuoka M, Jiang H, Evans S, Macgillivray C, Nightingale M, Perry S, Ferguson M, LeBlanc M, Paquette J, Patry L, Rideout AL, Thomas A, Orr A, McMaster CR, Michaud JL, Deal C, Langlois S, Superneau DW, Parkash S, Ludman M, Skidmore DL, Samuels ME. Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome. Nat Genet. 2011 Feb 27;43(4):360-4. doi: 10.1038/ng.777. PMID:21358631 doi:10.1038/ng.777
- ↑ Ishimi Y. A DNA helicase activity is associated with an MCM4, -6, and -7 protein complex. J Biol Chem. 1997 Sep 26;272(39):24508-13. PMID:9305914
- ↑ Wohlschlegel JA, Dwyer BT, Dhar SK, Cvetic C, Walter JC, Dutta A. Inhibition of eukaryotic DNA replication by geminin binding to Cdt1. Science. 2000 Dec 22;290(5500):2309-12. PMID:11125146 doi:10.1126/science.290.5500.2309
- ↑ Miotto B, Struhl K. JNK1 phosphorylation of Cdt1 inhibits recruitment of HBO1 histone acetylase and blocks replication licensing in response to stress. Mol Cell. 2011 Oct 7;44(1):62-71. doi: 10.1016/j.molcel.2011.06.021. PMID:21856198 doi:10.1016/j.molcel.2011.06.021
- ↑ Cook JG, Chasse DA, Nevins JR. The regulated association of Cdt1 with minichromosome maintenance proteins and Cdc6 in mammalian cells. J Biol Chem. 2004 Mar 5;279(10):9625-33. Epub 2003 Dec 11. PMID:14672932 doi:10.1074/jbc.M311933200
- ↑ Sugimoto N, Tatsumi Y, Tsurumi T, Matsukage A, Kiyono T, Nishitani H, Fujita M. Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding. J Biol Chem. 2004 May 7;279(19):19691-7. Epub 2004 Mar 1. PMID:14993212 doi:10.1074/jbc.M313175200
- ↑ Liu C, Wu R, Zhou B, Wang J, Wei Z, Tye BK, Liang C, Zhu G. Structural insights into the Cdt1-mediated MCM2-7 chromatin loading. Nucleic Acids Res. 2012 Apr;40(7):3208-17. doi: 10.1093/nar/gkr1118. Epub 2011, Dec 2. PMID:22140117 doi:http://dx.doi.org/10.1093/nar/gkr1118
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