CDT1 (Chromatin licensing and DNA replication factor 1) is a protein that in humans is encoded by the CDT1gene.[1][2][3][4] It is a licensing factor that functions to limit DNA from replicating more than once per cell cycle.
The protein encoded by this gene is a key licensing factor in the assembly of pre-replication complexes (pre-RC), which occurs during the G1 phase of the cell cycle. In the assembly of pre-RCs, origin recognition complexes (ORC1-6) recognize and bind to DNA replication origins. CDT1, along with the protein CDC6, are then recruited to the forming pre-RC, followed by minichromosome maintenance complexes (MCM2-7).[5]
The activity of CDT1 during the cell cycle is tightly regulated during the S phase by the protein geminin, which inhibits its, and by SCFSKP2, which ubiquinates the protein to tag it for proteasomal degradation.[6] This regulation is important in preventing relicensing, thus ensuring that DNA is only replicated once per cell cycle.
Orthologs
CDT1 belongs to a family of replication proteins conserved from yeast to humans. Examples of orthologs in other species include:
DNA replication factor CDT1 has been shown to interact with SKP2.[10] Cdt1 is recruited by the origin recognition complex in origin licensing. Null-mutations for CDT1 are lethal in yeast; the spores undergo mitosis without DNA replication. The overexpression of CDT1 causes rereplication in H. sapiens, which activates the CHK1 pathway, preventing entry into mitosis.[11]
References
↑Rialland M, Sola F, Santocanale C (March 2002). "Essential role of human CDT1 in DNA replication and chromatin licensing". J Cell Sci. 115 (Pt 7): 1435–40. PMID11896191.
↑Nishitani H, Taraviras S, Lygerou Z, Nishimoto T (November 2001). "The human licensing factor for DNA replication Cdt1 accumulates in G1 and is destabilized after initiation of S-phase". J Biol Chem. 276 (48): 44905–11. doi:10.1074/jbc.M105406200. PMID11555648.
↑Wohlschlegel JA, Dwyer BT, Dhar SK, Cvetic C, Walter JC, Dutta A (December 2000). "Inhibition of eukaryotic DNA replication by geminin binding to Cdt1". Science. 290 (5500): 2309–12. doi:10.1126/science.290.5500.2309. PMID11125146.
↑Nakajima H, Watanabe N, Shibata F, Kitamura T, Ikeda Y, Handa M (May 2006). "N-terminal region of CCAAT/enhancer-binding protein epsilon is critical for cell cycle arrest, apoptosis, and functional maturation during myeloid differentiation". J. Biol. Chem. 281 (20): 14494–502. doi:10.1074/jbc.M600575200. PMID16531405.
↑Maiorano D, Moreau J, Méchali M (April 2000). "XCDT1 is required for the assembly of pre-replicative complexes in Xenopus laevis". Nature. 404 (6778): 622–5. doi:10.1038/35007104. PMID10766247.
↑Li X, Zhao Q, Liao R, Sun P, Wu X (2003). "The SCF(Skp2) ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation". J. Biol. Chem. 278 (33): 30854–8. doi:10.1074/jbc.C300251200. PMID12840033.
↑Machida YJ, Dutta A (2005). "Cellular checkpoint mechanisms monitoring proper initiation of DNA replication". J. Biol. Chem. 280 (8): 6253–6. doi:10.1074/jbc.R400037200. PMID15591064.
Further reading
Xouri G, Dimaki M, Bastiaens PI, Lygerou Z (2007). "Cdt1 interactions in the licensing process: a model for dynamic spatiotemporal control of licensing". Cell Cycle. 6 (13): 1549–52. doi:10.4161/cc.6.13.4455. PMID17598984.
Andersson B, Wentland MA, Ricafrente JY, et al. (1996). "A "double adaptor" method for improved shotgun library construction". Anal. Biochem. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID8619474.
Nishitani H, Lygerou Z, Nishimoto T, Nurse P (2000). "The Cdt1 protein is required to license DNA for replication in fission yeast". Nature. 404 (6778): 625–8. doi:10.1038/35007110. PMID10766248.
Wohlschlegel JA, Dwyer BT, Dhar SK, et al. (2001). "Inhibition of eukaryotic DNA replication by geminin binding to Cdt1". Science. 290 (5500): 2309–12. doi:10.1126/science.290.5500.2309. PMID11125146.
Yanagi K, Mizuno T, You Z, Hanaoka F (2002). "Mouse geminin inhibits not only Cdt1-MCM6 interactions but also a novel intrinsic Cdt1 DNA binding activity". J. Biol. Chem. 277 (43): 40871–80. doi:10.1074/jbc.M206202200. PMID12192004.
Li X, Zhao Q, Liao R, et al. (2003). "The SCF(Skp2) ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation". J. Biol. Chem. 278 (33): 30854–8. doi:10.1074/jbc.C300251200. PMID12840033.
Cook JG, Chasse DA, Nevins JR (2004). "The regulated association of Cdt1 with minichromosome maintenance proteins and Cdc6 in mammalian cells". J. Biol. Chem. 279 (10): 9625–33. doi:10.1074/jbc.M311933200. PMID14672932.
Sugimoto N, Tatsumi Y, Tsurumi T, et al. (2004). "Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding". J. Biol. Chem. 279 (19): 19691–7. doi:10.1074/jbc.M313175200. PMID14993212.
Liu E, Li X, Yan F, et al. (2004). "Cyclin-dependent kinases phosphorylate human Cdt1 and induce its degradation". J. Biol. Chem. 279 (17): 17283–8. doi:10.1074/jbc.C300549200. PMID15004027.
Ramachandran N, Hainsworth E, Bhullar B, et al. (2004). "Self-assembling protein microarrays". Science. 305 (5680): 86–90. doi:10.1126/science.1097639. PMID15232106.
Saxena S, Yuan P, Dhar SK, et al. (2004). "A dimerized coiled-coil domain and an adjoining part of geminin interact with two sites on Cdt1 for replication inhibition". Mol. Cell. 15 (2): 245–58. doi:10.1016/j.molcel.2004.06.045. PMID15260975.
Kulartz M, Knippers R (2004). "The replicative regulator protein geminin on chromatin in the HeLa cell cycle". J. Biol. Chem. 279 (40): 41686–94. doi:10.1074/jbc.M405798200. PMID15284237.
