Alternative titles; symbols
HGNC Approved Gene Symbol: CDC45
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38): 22:19,479,466-19,520,612 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.21 | Meier-Gorlin syndrome 7 | 617063 | Autosomal recessive | 3 |
CDC45 is an essential component of the replication fork involved in DNA unwinding during replication elongation (Pacek et al., 2006).
By searching an EST database for homologs of yeast Cdc45, Saha et al. (1998) identified CDC45L cDNAs. The predicted 566-amino acid protein is 28% identical to yeast Cdc45. Both the yeast and human proteins contain a region of acidic amino acids and a putative bipartite nuclear localization signal. Western blot analysis of mammalian cell extracts revealed that the level of the 60-kD CDC45L protein is unchanged during the cell cycle. However, subcellular fractionation studies indicated that, as with MCM proteins, the association of CDC45L with the nuclear fraction diminishes as S phase progresses. Consistent with its role in the initiation of DNA replication, Saha et al. (1998) found that CDC45L coimmunoprecipitated with ORC2L (601182), a putative replication initiator.
Independently, McKie et al. (1998) isolated cDNAs encoding CDC45L, which they called CDC45L2. These authors reported that the human and mouse CDC45L proteins are 89% identical.
Saha et al. (1998) determined that the CDC45L gene contains 19 exons and spans 30 kb.
By fluorescence in situ hybridization and by inclusion within mapped clones, Saha et al. (1998) mapped the CDC45L gene to chromosome 22q11.2, within the DiGeorge syndrome (188400) critical region. They found that 1 copy of the gene is deleted in patients with DiGeorge syndrome.
Falck et al. (2002) demonstrated that experimental blockade of either the NBS1 (602667)-MRE11 (600814) function or the CHK2 (604373)-triggered events leads to a partial radioresistant DNA synthesis phenotype in human cells. In contrast, concomitant interference with NBS1-MRE11 and the CHK2-CDC25A (116947)-CDK2 (116953) pathways entirely abolishes inhibition of DNA synthesis induced by ionizing radiation, resulting in complete radioresistant DNA synthesis analogous to that caused by defective ATM (607585). In addition, CDK2-dependent loading of CDC45 onto replication origins, a prerequisite for recruitment of DNA polymerase, was prevented upon irradiation of normal or NBS1/MRE11-defective cells but not cells with defective ATM. Falck et al. (2002) concluded that in response to ionizing radiation, phosphorylation of NBS1 and CHK2 by ATM triggers 2 parallel branches of the DNA damage-dependent S-phase checkpoint that cooperate by inhibiting distinct steps of DNA replication.
In Xenopus egg extracts, Pacek et al. (2006) showed that the MCM2-7 complex (see 116945), the GINS complex (see GINS1; 610608), and Cdc45 were enriched at stalled replication forks. They proposed that these components unwind DNA and separate DNA strands at replication forks.
Maric et al. (2014) showed that the CMG helicase, composed of Cdc45/Mcm (see MCM7, 600592)/GINS, is ubiquitylated during the final stages of chromosome replication in S. cerevisiae, specifically on its Mcm7 subunit. The yeast F-box protein Dia2 is essential in vivo for ubiquitylation of CMG, and the SCF(Dia2) ubiquitin ligase (see 603134) is also required to ubiquitylate CMG in vitro on its Mcm7 subunit in extracts of S-phase yeast cells. Maric et al. (2014) concluded that their data identified 2 key features of helicase disassembly in budding yeast. First, there is an essential role for the F-box protein Dia2, which drives ubiquitylation of the CMG helicase on its Mcm7 subunit. Second, the Cdc48 (601023) segregase is required to break ubiquitylated CMG into its component parts. Once separated from GINS and Cdc45, the Mcm2-7 hexamer is less stable, so that all of the subunits of the CMG helicase are lost from the newly replicated DNA.
Yamagishi et al. (1999) found that the CDC45L gene is situated immediately telomeric of UFD1L (601754) and is transcribed in the opposite direction. They reported a unique patient with a de novo deletion beginning in the intron between exons 5 and 6 of CDC45L and deleting exons 1 to 3 of UFD1L; the patient had features typical of the 22q11 deletion syndrome.
In 12 affected individuals from 15 families who exhibited phenotypes ranging from syndromic craniosynostosis to classic Meier-Gorlin syndrome (MGORS7; 617063), Fenwick et al. (2016) identified homozygosity or compound heterozygosity for mutations in the CDC45L gene (see, e.g., 603465.0001-603465.0009). Functional analysis showed reduced CDC45L protein levels in patient cell lines compared to controls, suggesting that the mutations result in destabilization of the protein.
In a 28-year-old man from the United Kingdom with right unicoronal craniosynostosis, microtia, and urethral stricture (MGORS7; 617063), Fenwick et al. (2016) identified compound heterozygosity for a c.677A-G transition (c.677A-G, NM_003504.4) in the CDC45 gene, resulting in an asp226-to-gly (D226G) substitution at a conserved residue, and a c.318C-T transition in exon 4, resulting in a val106-to-val (V106V; 603465.0002) substitution within the alpha/beta domain-1. His unaffected parents and 2 unaffected brothers were each heterozygous for 1 of the mutations. Patient-derived RNA showed an increased ratio of exon 3/5 transcript to exon 3/4/5 cDNA product compared to controls, indicating skipping of exon 4 with the synonymous mutation. In patient lymphoblastoid cell lines, CDC45 levels were significantly lower than in controls and were reduced below 50%, indicating that both alleles contributed to the reduced protein levels.
For discussion of the c.318C-T transition (c.318C-T, NM_003504.4) in the CDC45 gene, resulting in a val106-to-val (V106V) substitution, that was found in compound heterozygous state in a patient with Meier-Gorlin syndrome-7 (MGORS7; 617063) by Fenwick et al. (2016), see 603465.0001.
In a 4.3-year-old girl with bicoronal craniosynostosis and anterior anus (MGORS7; 617063), Fenwick et al. (2016) identified compound heterozygosity for 2 missense mutations in the CDC45 gene: a c.226A-C (c.226A-C, NM_003504.4) transversion, resulting in an asn76-to-his (N76H) substitution within the alpha/beta domain-1, and a c.469C-T transition, resulting in an arg157-to-cys (R157C) substitution within the PHM domain. Her unaffected parents and 1 unaffected sister were each heterozygous for 1 of the mutations, both of which involved conserved residues. In patient lymphoblastoid cell lines, CDC45 levels were significantly lower than in controls and were reduced below 50%, indicating that both alleles contributed to the reduced protein levels.
For discussion of the c.469C-T transition (c.469C-T, NM_003504.4) in the CDC45 gene, resulting in an arg157-to-cys (R157C) substitution, that was found in compound heterozygous state in a patient with Meier-Gorlin syndrome-7 (MGORS7; 617063) by Fenwick et al. (2016), see 603465.0003.
In 3 patients from 2 Egyptian families with craniosynostosis, microtia, and patellar aplasia or hypoplasia (MGORS7; 617063), Fenwick et al. (2016) identified homozygosity for a c.1660C-T transition (c.1660C-T, NM_003504.4) in the CDC45 gene, resulting in an arg554-to-trp (R554W) substitution at a conserved residue within the alpha/beta domain-2. The unaffected parents were heterozygous for the mutation. The brother and half sister from the first family had craniosynostosis involving the coronal and sagittal sutures, whereas the girl from the second family had craniosynostosis involving the coronal and lambdoid sutures. All 3 patients exhibited cardiac anomalies, including atrial septal defect, ventricular septal defect, and atrioventricular canal, and 1 of the patients had anal stenosis.
In 2 Turkish brothers with microtia and patellar aplasia or hypoplasia, 1 of whom also exhibited bicoronal craniosynostosis (MGORS7; 617063), Fenwick et al. (2016) identified compound heterozygosity for a c.203A-G transition (c.203A-G, NM_003504.4) in exon 3 of the CDC45 gene, resulting in a gln68-to-arg (Q68R) substitution at a conserved residue in the alpha/beta domain-1, and a c.333C-T transition in exon 4, resulting in an asn111-to-asn (N111N; 603465.0007) substitution. Patient-derived RNA showed an increased ratio of exon 3/5 transcript to exon 3/4/5 cDNA product compared to controls, indicating skipping of exon 4 with the synonymous mutation. In patient lymphoblastoid cell lines, CDC45 levels were significantly lower than in controls and were reduced below 50%, indicating that both alleles contributed to the reduced protein levels.
For discussion of the c.333C-T transition (c.333C-T, NM_003504.4) in the CDC45 gene, resulting in an asn111-to-asn (N111N) substitution, that was found in compound heterozygous state in a patient with Meier-Gorlin syndrome-7 (MGORS7; 617063) by Fenwick et al. (2016), see 603465.0006.
In a male and a female fetus from a Dutch family with syndromic craniosynostosis (MGORS7; 617063), Fenwick et al. (2016) identified compound heterozygosity for 2 mutations in the CDC45 gene. The first was a c.893C-T transition (c.893C-T, NM_003504.4), resulting in an ala298-to-val (A298V) substitution at a conserved residue in the all-helix interdomain; the second was a c.(485+1_486-1)_(630+1_631-1) deletion (603465.0009) encompassing exon 5 (Ile115_Glu162del) of CDC45. The unaffected parents were each heterozygous for 1 of the mutations. In patient lymphoblastoid cell lines, CDC45 levels were significantly lower than in controls and were reduced below 50%, indicating that both alleles contributed to the reduced protein levels.
For discussion of the deletion (c.(485+1_486-1)_(630+1_631-1), NM_003504.4) encompassing exon 5 in the CDC45 gene that was found in compound heterozygous state in a patient with Meier-Gorlin syndrome-7 (MGORS7; 617063) by Fenwick et al. (2016), see 603465.0008.
Falck, J., Petrini, J. H. J., Williams, B. R., Lukas, J., Bartek, J. The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nature Genet. 30: 290-294, 2002. [PubMed: 11850621] [Full Text: https://doi.org/10.1038/ng845]
Fenwick, A. L., Kliszczak, M., Cooper, F., Murray, J., Sanchez-Pulido, L., Twigg, S. R. F., Goriely, A., McGowan, S. J., Miller, K. A., Taylor, I. B., Logan, C., WGS500 Consortium, and 22 others. Mutations in CDC45, encoding an essential component of the pre-initiation complex, cause Meier-Gorlin syndrome and craniosynostosis. Am. J. Hum. Genet. 99: 125-138, 2016. [PubMed: 27374770] [Full Text: https://doi.org/10.1016/j.ajhg.2016.05.019]
Maric, M., Maculins, T., De Piccoli, G., Labib, K. Cdc48 and a ubiquitin ligase drive disassembly of the CMG helicase at the end of DNA replication. Science 346: 1253596, 2014. Note: Electronic Article. [PubMed: 25342810] [Full Text: https://doi.org/10.1126/science.1253596]
McKie, J. M., Wadey, R. B., Sutherland, H. F., Taylor, C. L., Scambler, P. J. Direct selection of conserved cDNAs from the DiGeorge critical region: isolation of a novel CDC45-like gene. Genome Res. 8: 834-841, 1998. [PubMed: 9724329] [Full Text: https://doi.org/10.1101/gr.8.8.834]
Pacek, M., Tutter, A. V., Kubota, Y., Takisawa, H., Walter, J. C. Localization of MCM2-7, Cdc45, and GINS to the site of DNA unwinding during eukaryotic DNA replication. Molec. Cell 21: 581-587, 2006. [PubMed: 16483939] [Full Text: https://doi.org/10.1016/j.molcel.2006.01.030]
Saha, P., Thome, K. C., Yamaguchi, R., Hou, Z., Weremowicz, S., Dutta, A. The human homolog of Saccharomyces cerevisiae CDC45. J. Biol. Chem. 273: 18205-18209, 1998. [PubMed: 9660782] [Full Text: https://doi.org/10.1074/jbc.273.29.18205]
Yamagishi, H., Garg, V., Matsuoka, R., Thomas, T., Srivastava, D. A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Science 283: 1158-1161, 1999. [PubMed: 10024240] [Full Text: https://doi.org/10.1126/science.283.5405.1158]