DNA replication factor CDT1

CDT1 (Chromatin licensing and DNA replication factor 1) is a protein that in humans is encoded by the CDT1 gene.^[5][6][7][8] It is a licensing factor that functions to limit DNA from replicating more than once per cell cycle.

CDT1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2LE8, 2WVR
Identifiers
Aliases	CDT1, DUP, RIS2, chromatin licensing and DNA replication factor 1
External IDs	OMIM: 605525; MGI: 1914427; HomoloGene: 32650; GeneCards: CDT1; OMA:CDT1 - orthologs
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16q24.3 Start 88,803,789 bp[1] End 88,809,258 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8|8 E1 Start 123,294,754 bp[2] End 123,300,293 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of paranasal sinus oocyte gingival epithelium secondary oocyte ventricular zone ganglionic eminence mucosa of transverse colon gonad trabecular bone bone marrow Top expressed in fetal liver hematopoietic progenitor cell endocardial cushion tibiofemoral joint abdominal wall primitive streak condyle fossa Paneth cell vas deferens primary oocyte More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding protein binding chromatin binding DNA polymerase binding Cellular component cytosol nucleus nucleoplasm nuclear body chromosome, centromeric region chromosome kinetochore cytoplasm Biological process DNA replication checkpoint signaling DNA replication cell cycle regulation of nuclear cell cycle DNA replication regulation of transcription involved in G1/S transition of mitotic cell cycle regulation of DNA-dependent DNA replication initiation chromosome segregation attachment of mitotic spindle microtubules to kinetochore mitotic cell cycle positive regulation of protein-containing complex assembly regulation of chromosome organization positive regulation of chromatin binding cell division kinetochore organization DNA replication preinitiation complex assembly response to sorbitol deactivation of mitotic spindle assembly checkpoint regulation of DNA replication origin binding negative regulation of protein localization to kinetochore positive regulation of protein localization to kinetochore positive regulation of DNA-dependent DNA replication positive regulation of mediator complex assembly G1/S transition of mitotic cell cycle positive regulation of DNA replication mitotic cytokinesis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 81620 67177 Ensembl ENSG00000167513 ENSMUSG00000006585 UniProt Q9H211 Q8R4E9 RefSeq (mRNA) NM_030928 NM_026014 RefSeq (protein) NP_112190 NP_080290 Location (UCSC) Chr 16: 88.8 – 88.81 Mb Chr 8: 123.29 – 123.3 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Role in pre-replication complexes

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).^[9]

The activity of CDT1 during the cell cycle is tightly regulated during the S phase by the protein geminin, which inhibits it, and by SCF^SKP2, which ubiquinates the protein to tag it for proteasomal degradation.^[10] 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:

• S. pombe – CDT1 (CDC10-dependent transcript 1)^[11]
• Drosophila melanogaster – 'double parked' or Dup^[12]
• Xenopus laevis - CDT1^[13]

Interactions

DNA replication factor CDT1 has been shown to interact with SKP2.^[14] 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.^[15]

References

1. GRCh38: Ensembl release 89: ENSG00000167513 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000006585 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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. doi:10.1242/jcs.115.7.1435. PMID 11896191.
6. 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. PMID 11555648.
7. "Entrez Gene: CDT1 chromatin licensing and DNA replication factor 1".
8. "CDT1 gene". Genetics Home Reference. Retrieved 2018-07-19.
9. 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.{{cite book}}: CS1 maint: location missing publisher (link)
10. 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. Bibcode:2000Sci...290.2309W. doi:10.1126/science.290.5500.2309. PMID 11125146.
11. Hofmann JF, Beach D (January 1994). "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. doi:10.1002/j.1460-2075.1994.tb06277.x. PMC 394824. PMID 8313888.
12. 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. PMID 16531405.
13. 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. Bibcode:2000Natur.404..622M. doi:10.1038/35007104. PMID 10766247. S2CID 4416138.
14. 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. PMID 12840033.
15. 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. PMID 15591064.

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. PMID 17598984.
• 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. PMID 8619474.
• Yu W, Andersson B, Worley KC, et al. (1997). "Large-scale concatenation cDNA sequencing". Genome Res. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
• 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. Bibcode:2000Natur.404..625N. doi:10.1038/35007110. PMID 10766248. S2CID 205005540.
• Whittaker AJ, Royzman I, Orr-Weaver TL (2000). "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. doi:10.1101/gad.14.14.1765. PMC 316778. PMID 10898791.
• Wohlschlegel JA, Dwyer BT, Dhar SK, et al. (2001). "Inhibition of eukaryotic DNA replication by geminin binding to Cdt1". Science. 290 (5500): 2309–12. Bibcode:2000Sci...290.2309W. doi:10.1126/science.290.5500.2309. PMID 11125146.
• 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. PMID 12192004.
• Bermejo R, Vilaboa N, Calés C (2003). "Regulation of CDC6, geminin, and CDT1 in human cells that undergo polyploidization". Mol. Biol. Cell. 13 (11): 3989–4000. doi:10.1091/mbc.E02-04-0217. PMC 133609. PMID 12429841.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "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. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• 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. PMID 12840033.
• 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. PMID 14672932.
• 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. PMID 14993212.
• 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. PMID 15004027.
• Ramachandran N, Hainsworth E, Bhullar B, et al. (2004). "Self-assembling protein microarrays". Science. 305 (5680): 86–90. Bibcode:2004Sci...305...86R. doi:10.1126/science.1097639. PMID 15232106. S2CID 20936301.
• Ballabeni A, Melixetian M, Zamponi R, et al. (2005). "Human geminin promotes pre-RC formation and DNA replication by stabilizing CDT1 in mitosis". EMBO J. 23 (15): 3122–32. doi:10.1038/sj.emboj.7600314. PMC 514931. PMID 15257290.
• 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. PMID 15260975.
• 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. PMID 15284237.
• Beausoleil SA, Jedrychowski M, Schwartz D, et al. (2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proc. Natl. Acad. Sci. U.S.A. 101 (33): 12130–5. Bibcode:2004PNAS..10112130B. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.

External links

• 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.