DNA replication factor CDT1

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Identifiers
Aliases|
External IDs| GeneCards: [1]
Orthologs
Species| Human| Mouse
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Wikidata
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CDT1 (Chromatin licensing and DNA replication factor 1) is a protein that in humans is encoded by the CDT1 gene.[1][2][3][4] It is a licensing factor that functions to limit DNA from replicating more than once per cell cycle.

## Contents

* 1 Role in pre-replication complexes
* 2 Orthologs
* 3 Interactions
* 4 References
* 5 Further reading

## Role in pre-replication complexes

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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

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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)[7]
* Drosophila melanogaster – 'double parked' or Dup[8]
* Xenopus laevis \- CDT1[9]

## Interactions

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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

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1. ↑ 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. PMID 11896191.
2. ↑ 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.
3. ↑ "Entrez Gene: CDT1 chromatin licensing and DNA replication factor 1".
4. ↑ Reference, Genetics Home. "CDT1 gene". Genetics Home Reference. Retrieved 2018-07-19.
5. ↑ 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.
6. ↑ 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. PMID 11125146.
7. ↑ 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. PMC 394824. PMID 8313888.
8. ↑ 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.
9. ↑ 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. PMID 10766247.
10. ↑ 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.
11. ↑ 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

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* 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. doi:10.1038/35007110. PMID 10766248.
* 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. 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. 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. 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. doi:10.1126/science.1097639. PMID 15232106.
* 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. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.

* v
* t
* e

DNA replication (comparing Prokaryotic to Eukaryotic)

Initiation|

| Prokaryotic
(initiation)|

* Pre-replication complex

* dnaC
* Cdc6

* Helicase
* dnaA
* dnaB
* T7

* Primase
* dnaG

|

Eukaryotic
(preparation in
G1 phase)|

* Pre-replication complex

* Origin recognition complex
* ORC1
* ORC2
* ORC3
* ORC4
* ORC5
* ORC6

* Cdc6

* Cdt1

* Minichromosome maintenance
* MCM2
* MCM3
* MCM4
* MCM5
* MCM6
* MCM7

* Licensing factor

* Autonomously replicating sequence

* Single-strand binding protein
* SSBP2
* SSBP3
* SSBP4

* RNase H
* RNASEH1
* RNASEH2A

* Helicase: HFM1

* Primase: PRIM1
* PRIM2

Both|

* Origin of replication/Ori/Replicon

* Replication fork
* Lagging and leading strands
* Okazaki fragments
* Primer

Replication|

| Prokaryotic
(elongation)|

* DNA polymerase III holoenzyme
* dnaC
* dnaE
* dnaH
* dnaN
* dnaQ
* dnaT
* dnaX
* holA
* holB
* holC
* holD
* holE
*   * Replisome
* DNA ligase
* DNA clamp
* Topoisomerase
* DNA gyrase

* Prokaryotic DNA polymerase: DNA polymerase I
* Klenow fragment

|

Eukaryotic
(synthesis in
S phase)|

* Replication factor C
* RFC1
* Flap endonuclease
* FEN1
* Topoisomerase
* Replication protein A
* RPA1

* Eukaryotic DNA polymerase:
* alpha
* POLA1
* POLA2
* PRIM1
* PRIM2
* delta
* POLD1
* POLD2
* POLD3
* POLD4
* epsilon
* POLE
* POLE2
* POLE3
* POLE4

* DNA clamp
* PCNA

* Control of chromosome duplication

Both|

* Movement: Processivity
* DNA ligase

Termination|

* Telomere: Telomerase
* TERT
* TERC
* DKC1

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