CDT1

CDT1（chromatin licensing and DNA replication factor 1）は、ヒトではCDT1遺伝子によってコードされているタンパク質である。 CDT1は、細胞周期のG1期に行われる複製前複合体（pre-RC）の組み立てにおける、重要なライセンス因子（英語版）である。pre-RCの組み立て過程では、複製起点認識複合体（ORC1からORC6）がDNAの複製起点を認識して結合する。その後、CDT1はCDC6（英語版）とともに形成中のpre-RCへリクルートされ、そしてMCM複合体（MCM2からMCM7）がリクルートされる。 CDT1の活性は細胞周期中で緊密に調節されている。S期の間はジェミニンによって阻害され、またSCFSKP2によってユビキチン化されプロテアソーム分解が行われる。この調節は再ライセンス化の防止に重要であり、DNAが各細胞周期に1度だけ複製されるよう保証している。 CDT1は酵母からヒトまで保存された複製タンパク質ファミリーに属する。他の生物種におけるオルソログの例を次に挙げる。 分裂酵母Schizosaccharomyces pombe – CDT1 (CDC10-dependent transcript 1) キイロショウジョウバエDrosophila melanogaster – 'double parked' or Dup アフリカツメガエルXenopus laevis – XCDT1 CDT1はSKP2と相互作用することが示されている。CDT1は複製起点のライセンス化の際に複製起点認識複合体によってリクルートされる。酵母ではCDT1のヌル変異は致死であり、胞子ではDNA複製を行うことなく有糸分裂が生じる。ヒトでは、CDT1の過剰発現によってDNA再複製が引き起こされ、Chk1経路が活性化されることで有糸分裂の開始が阻害される。 ^ a b c GRCh38: Ensembl release 89: ENSG00000167513 - Ensembl, May 2017 ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000006585 - Ensembl, May 2017 ^ Human PubMed Reference: ^ Mouse PubMed Reference: ^ “Essential role of human CDT1 in DNA replication and chromatin licensing”. J Cell Sci 115 (Pt 7): 1435–40. (March 2002). doi:10.1242/jcs.115.7.1435. PMID 11896191.  ^ “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. (November 2001). doi:10.1074/jbc.M105406200. PMID 11555648.  ^ Hoffman, Ronald; Benz Jr., Edward J.; Silberstein, Leslie E.; Heslop, Helen; Weitz, Jeffrey I.; Anastasi, John; Salama, Mohamed E.; Abutalib, Syed A. (2018). Hematology : basic principles and practice. Hoffman, Ronald, 1945-, Benz, Edward J., Jr.,, Silberstein, Leslie E.,, Heslop, Helen,, Weitz, Jeffrey I.,, Anastasi, John (Seventh ed.). Philadelphia, PA. pp. Chapter 17, 176–185. ISBN 9780323509398. OCLC 1001961209  ^ “Inhibition of eukaryotic DNA replication by geminin binding to Cdt1”. Science 290 (5500): 2309–12. (December 2000). Bibcode: 2000Sci...290.2309W. doi:10.1126/science.290.5500.2309. PMID 11125146.  ^ “cdt1 is an essential target of the Cdc10/Sct1 transcription factor: requirement for DNA replication and inhibition of mitosis”. EMBO J. 13 (2): 425–34. (January 1994). doi:10.1002/j.1460-2075.1994.tb06277.x. PMC 394824. PMID 8313888. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC394824/.  ^ “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. (May 2006). doi:10.1074/jbc.M600575200. PMID 16531405.  ^ “XCDT1 is required for the assembly of pre-replicative complexes in Xenopus laevis.”. Nature 404 (6778): 622–5. (April 2000). Bibcode: 2000Natur.404..622M. doi:10.1038/35007104. PMID 10766247.  ^ “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. (2003). doi:10.1074/jbc.C300251200. PMID 12840033.  ^ “Cellular checkpoint mechanisms monitoring proper initiation of DNA replication”. J. Biol. Chem. 280 (8): 6253–6. (2005). doi:10.1074/jbc.R400037200. PMID 15591064.  “Cdt1 interactions in the licensing process: a model for dynamic spatiotemporal control of licensing.”. Cell Cycle 6 (13): 1549–52. (2007). doi:10.4161/cc.6.13.4455. PMID 17598984.  “A "double adaptor" method for improved shotgun library construction.”. Anal. Biochem. 236 (1): 107–13. (1996). doi:10.1006/abio.1996.0138. PMID 8619474.  “Large-scale concatenation cDNA sequencing.”. Genome Res. 7 (4): 353–8. (1997). doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC139146/.  “The Cdt1 protein is required to license DNA for replication in fission yeast.”. Nature 404 (6778): 625–8. (2000). Bibcode: 2000Natur.404..625N. doi:10.1038/35007110. PMID 10766248.  “Drosophila double parked: a conserved, essential replication protein that colocalizes with the origin recognition complex and links DNA replication with mitosis and the down-regulation of S phase transcripts.”. Genes Dev. 14 (14): 1765–76. (2000). doi:10.1101/gad.14.14.1765. PMC 316778. PMID 10898791. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC316778/.  “Inhibition of eukaryotic DNA replication by geminin binding to Cdt1.”. Science 290 (5500): 2309–12. (2001). Bibcode: 2000Sci...290.2309W. doi:10.1126/science.290.5500.2309. PMID 11125146.  “Mouse geminin inhibits not only Cdt1-MCM6 interactions but also a novel intrinsic Cdt1 DNA binding activity.”. J. Biol. Chem. 277 (43): 40871–80. (2002). doi:10.1074/jbc.M206202200. PMID 12192004.  “Regulation of CDC6, geminin, and CDT1 in human cells that undergo polyploidization.”. Mol. Biol. Cell 13 (11): 3989–4000. (2003). doi:10.1091/mbc.E02-04-0217. PMC 133609. PMID 12429841. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC133609/.  “Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.”. Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. (2003). Bibcode: 2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC139241/.  “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. (2003). doi:10.1074/jbc.C300251200. PMID 12840033.  “The regulated association of Cdt1 with minichromosome maintenance proteins and Cdc6 in mammalian cells.”. J. Biol. Chem. 279 (10): 9625–33. (2004). doi:10.1074/jbc.M311933200. PMID 14672932.  “Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding.”. J. Biol. Chem. 279 (19): 19691–7. (2004). doi:10.1074/jbc.M313175200. PMID 14993212.  “Cyclin-dependent kinases phosphorylate human Cdt1 and induce its degradation.”. J. Biol. Chem. 279 (17): 17283–8. (2004). doi:10.1074/jbc.C300549200. PMID 15004027.  “Self-assembling protein microarrays.”. Science 305 (5680): 86–90. (2004). Bibcode: 2004Sci...305...86R. doi:10.1126/science.1097639. PMID 15232106.  “Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis.”. EMBO J. 23 (15): 3122–32. (2005). doi:10.1038/sj.emboj.7600314. PMC 514931. PMID 15257290. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC514931/.  “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. (2004). doi:10.1016/j.molcel.2004.06.045. PMID 15260975.  “The replicative regulator protein geminin on chromatin in the HeLa cell cycle.”. J. Biol. Chem. 279 (40): 41686–94. (2004). doi:10.1074/jbc.M405798200. PMID 15284237.  “Large-scale characterization of HeLa cell nuclear phosphoproteins.”. Proc. Natl. Acad. Sci. U.S.A. 101 (33): 12130–5. (2004). Bibcode: 2004PNAS..10112130B. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC514446/.  Overview of all the structural information available in the PDB for UniProt: Q9H211 (Human DNA replication factor Cdt1) at the PDBe-KB. Overview of all the structural information available in the PDB for UniProt: Q8R4E9 (Mouse DNA replication factor Cdt1) at the PDBe-KB. 表示 編集