Alternative titles; symbols
HGNC Approved Gene Symbol: CDT1
Cytogenetic location: 16q24.3 Genomic coordinates (GRCh38): 16:88,803,789-88,809,258 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
16q24.3 | Meier-Gorlin syndrome 4 | 613804 | Autosomal recessive | 3 |
Whittaker et al. (2000) identified a Drosophila gene, which they called 'double parked,' or Dup, that is essential for DNA replication and belongs to a family of replication proteins conserved from S. pombe to humans. Strong mutations in Dup were found to cause embryonic lethality, preceded by a failure to undergo S phase during the postblastoderm divisions. The authors showed that Dup is also required for DNA replication in the adult ovary, establishing that it is needed for DNA replication at multiple stages of development.
Geminin (602842) is a protein that inhibits DNA replication by preventing the loading of the minichromosome maintenance (MCM) complex on chromatin. Wohlschlegel et al. (2000) raised antibodies to bacterially expressed His6-geminin and identified DUP, which they called CDT1, as its target. They found that the human DUP cDNA reported by Whittaker et al. (2000) had a frameshift error that resulted in the deletion of amino acids 1 to 145. Wohlschlegel et al. (2000) determined that human CDT1 is a 65-kD protein that contains 546 amino acids and coimmunoprecipitates with geminin. Inhibition of DNA replication by geminin in cell-free cDNA replication extracts could be reversed by the addition of excess CDT1. In the normal cell cycle, CDT1 is present only in G1 and S phases, whereas geminin is present in S and G2 phases. Wohlschlegel et al. (2000) concluded that their results suggest that geminin inhibits inappropriate origin firing by targeting CDT1.
Zhong et al. (2003) showed that the CUL4 ubiquitin ligase (see 603137) temporally restricts DNA replication licensing in Caenorhabditis elegans. Inactivation of CUL4 causes massive DNA rereplication, producing cells with up to 100C DNA content. The C. elegans ortholog of the replication-licensing factor Cdt1 is required for DNA replication. C. elegans CDT1 is present in G1-phase nuclei but disappears as cells enter S phase. In cells lacking CUL4, CDT1 levels failed to decrease during S phase and instead remained constant in the rereplicating cells. Removal of 1 genomic copy of CDT1 suppressed the CUL4 rereplication phenotype. Zhong et al. (2003) proposed that CUL4 prevents aberrant reinitiation of DNA replication, at least in part, by facilitating the degradation of CDT1.
Initiation of DNA replication requires the assembly of a prereplication complex (pre-RC) in late mitosis and G1, with sequential loading of the origin recognition complex (see ORC1; 601902), CDC6 (602627), CDT1, and the MCM2-7 complex (see MCM2; 116945) onto replication origins. Upon initiation of DNA replication, the pre-RC is disassembled, and CDT1 and CDC6 are released from the origins to prevent rereplication. Using human cell lines, Shen et al. (2012) showed that ORCA (LRWD1; 615617) was required for pre-RC assembly and replication initiation. Knockdown of ORCA via small interfering RNA reduced association of ORC and MCM2-7 with chromatin and caused failure of cell cycle progression through S phase. ORCA associated dynamically with different pre-RC components during the cell cycle: it associated with ORC and CDT1 at G1, with ORC(2-5) and geminin in S phase, and with ORC(2-5), phosphorylated CDT1, and phosphorylated geminin during mitosis. ORCA interacted directly with ORC2 (601182), CDT1, and geminin, and ORC2 was required for ORCA stability. Overexpression of geminin reduced the affinity of CDT1 for ORCA, and loss of association between ORCA and CDT1 appeared to be a key step in disassembling the pre-RC at the end of G1 phase.
Crystal Structure
Lee et al. (2004) described the crystal structure of the mouse geminin (602842)-Cdt1 complex using a truncated geminin involving residues 79-157 and a truncated Cdt1 including residues 172-368. The N-terminal region of a coiled-coil dimer of truncated geminin interacted with both N-terminal and C-terminal parts of truncated Cdt1. The primary interface relied on the steric complementarity between the truncated geminin dimer and hydrophobic face of the 2 short N-terminal helices of truncated Cdt1 and, in particular, pro181, ala182, tyr183, phe186, and leu189. Lee et al. (2004) concluded that the crystal structure, in conjunction with their biochemical data, indicated that the N-terminal region of truncated geminin might be required to anchor truncated Cdt1, and the C-terminal region of truncated geminin prevents access of the MCM complex to truncated Cdt1 through steric hindrance.
In 7 patients from 5 families with the Meier-Gorlin syndrome-4 form of microcephalic primordial dwarfism (MGORS4; 613804), Bicknell et al. (2011) identified compound heterozygosity for missense, nonsense, and splice site mutations in the CDT1 gene (see, e.g., 605525.0001-605525.0004).
In a 15-year-old girl with Meier-Gorlin syndrome who was negative for mutation in the ORC4 gene, Guernsey et al. (2011) sequenced candidate genes encoding ORC complex or pathway-associated proteins and identified homozygosity for a missense mutation in the CDT1 gene (605525.0005).
In 4 patients from 2 families with Meier-Gorlin syndrome-4 (MGORS4; 613804), including 3 sibs who were previously reported by Feingold (2002), Bicknell et al. (2011) identified compound heterozygosity for 2 mutations in the CDT1 gene: a 1385G-A transition in exon 9, resulting in an arg462-to-gln (R462Q) substitution at a conserved residue in the C-terminal winged helix domain, and a 1560C-A transversion in exon 10, resulting in a tyr520-to-ter (Y520X; 605525.0002) substitution, predicted to cause premature termination of the protein. The unaffected parents from both families were each heterozygous for 1 of the mutations, respectively. In a proband from another family with Meier-Gorlin syndrome, Bicknell et al. (2011) identified compound heterozygosity for R462Q and a splice site mutation in the CDT1 gene (605525.0003). None of the mutations were found in 380 control chromosomes.
For discussion of the tyr520-to-ter (Y520X) mutation in the CDT1 gene that was found in compound heterozygous state in patients with Meier-Gorlin syndrome-4 (MGORS4; 613804) by Bicknell et al. (2011), see 605525.0001.
In a 4.3-year-old girl with Meier-Gorlin syndrome-4 (MGORS4; 613804), Bicknell et al. (2011) identified compound heterozygosity for mutations in the CDT1 gene: a 351G-C transversion in the exon 2 splice site and the R462Q missense mutation (605525.0001).
In an unrelated 7-year-old girl with Meier-Gorlin syndrome, Bicknell et al. (2011) identified compound heterozygosity for the 351G-C splice site mutation and a 196G-A transition in exon 1 of the CDT1 gene, resulting in an ala66-to-thr (A66T) substitution (605525.0004). Neither mutation was found in 380 control chromosomes.
For discussion of the ala66-to-thr (A66T) mutation in the CDT1 gene that was found in compound heterozygous state in a patient with Meier-Gorlin syndrome (MGORS4; 613804) by Bicknell et al. (2011), see 605525.0003.
In a 15-year-old girl with Meier-Gorlin syndrome (MGORS4; 613804), previously reported by Bongers et al. (2001), Guernsey et al. (2011) identified homozygosity for a glu468-to-lys (E468K) substitution at a conserved residue in the C-terminal region of the CDT1 protein, which is believed to interact with the minichromosome maintenance complex during origin recognition. Her consanguineous Cajun parents were heterozygous for the mutation, which was not found in controls, including some of Acadian ethnicity.
Bicknell, L. S., Bongers, E. M. H. F., Leitch, A., Brown, S., Schoots, J., Harley, M. E., Aftimos, S., Al-Aama, J. Y., Bober, M., Brown, P. A. J., van Bokhoven, H., Dean, J., and 15 others. Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nature Genet. 43: 356-359, 2011. [PubMed: 21358632] [Full Text: https://doi.org/10.1038/ng.775]
Bongers, E. M. H. F., Opitz, J. M., Fryer, A., Sarda, P., Hennekam, R. C. M., Hall, B. D., Superneau, D. W., Harbison, M., Poss, A., van Bokhoven, H., Hamel, B. C. J., Knoers, N. V. A. M. Meier-Gorlin syndrome: report of eight additional cases and review. Am. J. Med. Genet. 102: 115-124, 2001. [PubMed: 11477602] [Full Text: https://doi.org/10.1002/ajmg.1452]
Feingold, M. Meier-Gorlin syndrome. (Letter) Am. J. Med. Genet. 109: 338 only, 2002. [PubMed: 11992493] [Full Text: https://doi.org/10.1002/ajmg.10315]
Guernsey, D. L., Matsuoka, M., Jiang, H., Evans, S., Macgillivray, C., Nightingale, M., Perry, S., Ferguson, M., LeBlanc, M., Paquette, J., Patry, L., Rideout, A. L., and 11 others. Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome. Nature Genet. 43: 360-364, 2011. [PubMed: 21358631] [Full Text: https://doi.org/10.1038/ng.777]
Lee, C., Hong, B., Choi, J. M., Kim, Y., Watanabe, S., Ishimi, Y., Enomoto, T., Tada, S., Kim, Y., Cho, Y. Structural basis for inhibition of the replication licensing factor Cdt1 by geminin. Nature 430: 913-917, 2004. [PubMed: 15286659] [Full Text: https://doi.org/10.1038/nature02813]
Shen, Z., Chakraborty, A., Jain, A., Giri, S., Ha, T., Prasanth, K. V., Prasanth, S. G. Dynamic association of ORCA with prereplicative complex components regulates DNA replication initiation. Molec. Cell. Biol. 32: 3107-3120, 2012. [PubMed: 22645314] [Full Text: https://doi.org/10.1128/MCB.00362-12]
Whittaker, A. J., Royzman, I., Orr-Weaver, T. L. 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: 1765-1776, 2000. [PubMed: 10898791]
Wohlschlegel, J. A., Dwyer, B. T., Dhar, S. K., Cvetic, C., Walter, J. C., Dutta, A. Inhibition of eukaryotic DNA replication by geminin binding to Cdt1. Science 290: 2309-2312, 2000. [PubMed: 11125146] [Full Text: https://doi.org/10.1126/science.290.5500.2309]
Zhong, W., Feng, H., Santiago, F. E., Kipreos, E. T. CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing. Nature 423: 885-889, 2003. [PubMed: 12815436] [Full Text: https://doi.org/10.1038/nature01747]