Alternative titles; symbols
HGNC Approved Gene Symbol: CIZ1
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38): 9:128,166,065-128,204,222 (from NCBI)
Using a modified yeast 2-hybrid screen to identify proteins that interact with the cyclin E (123837)/p21(Cip1) (CDKN1A; 116899) complex, Mitsui et al. (1999) cloned CIZ1 from a human B-cell cDNA library. By 5-prime RACE of human thymus or embryonic kidney cell cDNA libraries, they obtained a full-length clone. The deduced 898-amino acid protein contains 2 glutamine-rich domains, 3 C2H2-type zinc finger motifs, an acidic domain, and a C-terminal matrin (MATR3; 164015)-homologous domain 3 (MH3). Northern blot analysis detected CIZ1 in most human cell lines and mouse tissues examined, with highest expression in mouse testis and kidney. Western blot analysis detected proteins of 120 and 95 kD in most tissues. In a human osteosarcoma cell line, the 95-kD form predominated in detergent extracts and the 120-kD form was present in detergent-resistant cell nuclei. Mitsui et al. (1999) were unable to identify CIZ1 homologs in yeast, nematode, or fly databases, suggesting that CIZ1 is vertebrate-specific.
Using a transformation assay selecting for human medulloblastoma cDNAs that caused solid tumor formation in nude mice, Warder and Keherly (2003) cloned CIZ1, which they designated NP94. They also identified a CIZ1 splice variant that encodes a protein lacking amino acids 96 to 119 and amino acids 196 to 200. Northern blot analysis detected a 3-kb CIZ1 transcript with highest expression in pancreas, followed by brain, kidney, and placenta. Weakest expression was detected in liver, skeletal muscle, heart, and lung. Within the brain, highest expression was detected in cerebellum, and weakest expression was in spinal cord. CIZ1 was detected at high levels in ependymomas, medulloblastomas, and gliomas. CIZ1 localized in the nucleus of transfected COS-7 cells in 2 patterns: a diffuse pattern that excluded nucleoli and a punctate pattern where CIZ1 colocalized with DNA.
Coverley et al. (2005) stated that the full-length mouse Ciz1 protein contains 716 amino acids and shares about 70% overall homology with human CIZ1. They also identified an embryonic variant of mouse Ciz1 that is generated by alternative splicing of exons 2/3, 6, and 8.
Xiao et al. (2012) identified 2 CIZ1 isoforms that differ at variable exon 8 in human adult and fetal brain. Both isoforms were present in cerebellum, cerebral cortex, substantia nigra, and putamen of adult human brain.
By analyzing the interactions between truncated proteins, Mitsui et al. (1999) showed that a region of CIZ1, including the first zinc finger motif, bound to the N-terminal CDK2 (116953)-interacting domain of p21(Cip1) and that the interaction was disrupted by overexpression of CDK2. When CIZ1 and p21(Cip1) were individually overexpressed in human osteosarcoma cells, they localized primarily to the nucleus. However, overexpression of CIZ1 induced cytoplasmic distribution of p21(Cip1), suggesting that CIZ1 regulates the cellular localization of p21(Cip1).
Warder and Keherly (2003) determined that CIZ1 recognizes the consensus DNA sequence ARYSR(0-2)YYAC.
Using a cell-free system that reconstituted initiation of DNA replication, Coverley et al. (2005) identified mouse Ciz1. In cell-free experiments, Ciz1 increased the number of nuclei that initiated DNA replication. In intact wildtype and p21(Cip1)-null cells, Ciz1 stimulated DNA synthesis. Mutation of a putative cyclin-dependent kinase phosphorylation site at thr191 and thr192 altered Ciz1 activity in vitro. Consistent with a role in DNA replication, endogenous Ciz1 was present in nuclear foci that colocalized with Pcna (176740) during S phase, and targeted depletion of Ciz1 retrained cell proliferation by inhibiting entry into S phase. Ciz1-depleted cells accumulated chromatin-bound Mcm3 (602693) and Pcna but failed to synthesize DNA efficiently. Coverley et al. (2005) concluded that CIZ1 promotes DNA replication after replication complex formation.
Den Hollander et al. (2006) found that CIZ1 is an estrogen-responsive gene. CIZ1 coregulated the estrogen receptor (see ESR1; 133430) by enhancing ESR transactivation activity and promoting the recruitment of the ESR complex to target genes. CIZ1 overexpression conferred estrogen hypersensitivity and promoted growth rate, anchorage independence, and tumorigenic properties in breast cancer cells.
By radiation hybrid analysis and FISH, Gilley and Fried (1999) mapped the CIZ1 gene to chromosome 9q34.
For discussion of a possible association between dystonia (see 614860) and mutation in the CIZ1 gene, see 611420.0001.
This variant is classified as a variant of unknown significance because its contribution to dystonia (see 614860) has not been confirmed.
In affected members of a large Caucasian family with autosomal dominant cervical dystonia, Xiao et al. (2012) identified a heterozygous 790A-G transition at a highly conserved exon splicing enhancer site in exon 7 of the CIZ1 gene, resulting in a ser264-to-gly (S264G) substitution in a putative nuclear localization signal. The mutation was identified by exome sequencing. A minigene assay showed that the CIZ1 790A-G and wildtype CIZ1 constructs produced several bands of identical nucleotide sequences, but in differing amounts. In particular, a splice variant only containing exons 7 and 8 was significantly more abundant in wildtype cells, and an exon 7-only variant was barely detectable in 790A-G cells. These findings suggested that the 790A-G mutation affects splicing patterns. In lymphoblastoid cell lines, the 790A-G mutation had no effects on overall expression of CIZ1 and minimal effects on the ratio of isoform 1 and isoform 2 of the CIZ1 gene, which differ at variable exon 8. In HEK293 cells, the S264G protein entered the nuclei and formed subnuclear foci, but the particle size and number differed compared to wildtype subnuclear foci. Another heterozygous variant in the CIZ1 gene, a 1730C-T transition, resulting in a ser577-to-phe (S577F) substitution, was also identified in affected family members, but this residue is only partially conserved and was predicted to be benign in 2 of 3 prediction programs. All affected individuals also carried a heterozygous 4-bp deletion (2385delAAAG) in the SETX gene (608465), also on chromosome 9q34; the SETX variant was not seen in 724 normal controls. Although SETX mutations may cause neurologic disorders, Xiao et al. (2012) noted that heterozygous loss-of-function mutations in the SETX gene had not been reported and they therefore concluded that the SETX mutation was probably benign in this family.
Coverley, D., Marr, J., Ainscough, J. Ciz1 promotes mammalian DNA replication. J. Cell Sci. 118: 101-112, 2005. [PubMed: 15585571] [Full Text: https://doi.org/10.1242/jcs.01599]
den Hollander, P., Rayala, S. K., Coverley, D., Kumar, R. Ciz1, a novel DNA-binding coactivator of the estrogen receptor alpha, confers hypersensitivity to estrogen action. Cancer Res. 66: 11021-11029, 2006. [PubMed: 17108141] [Full Text: https://doi.org/10.1158/0008-5472.CAN-06-2336]
Gilley, J., Fried, M. Extensive gene order differences within regions of conserved synteny between the Fugu and human genomes: implications for chromosomal evolution and the cloning of disease genes. Hum. Molec. Genet. 8: 1313-1320, 1999. [PubMed: 10369878] [Full Text: https://doi.org/10.1093/hmg/8.7.1313]
Mitsui, K., Matsumoto, A., Ohtsuka, S., Ohtsubo, M., Yoshimura, A. Cloning and characterization of a novel p21(Cip1/Waf1)-interacting zinc finger protein, Ciz1. Biochem. Biophys. Res. Commun. 264: 457-464, 1999. [PubMed: 10529385] [Full Text: https://doi.org/10.1006/bbrc.1999.1516]
Warder, D. E., Keherly, M. J. Ciz1, Cip1 interacting zinc finger protein 1 binds the consensus DNA sequence ARYSR(0-2)YYAC. J. Biomed. Sci. 10: 406-417, 2003. [PubMed: 12824700] [Full Text: https://doi.org/10.1007/BF02256432]
Xiao, J., Uitti, R. J., Zhao, Y., Vemula, S. R., Perlmutter, J. S., Wszolek, Z. K., Maraganore, D. M., Auburger, G., Leube, B., Lehnhoff, K., LeDoux, M. S. Mutations in CIZ1 cause adult onset primary cervical dystonia. Ann. Neurol. 71: 458-469, 2012. [PubMed: 22447717] [Full Text: https://doi.org/10.1002/ana.23547]