Alternative titles; symbols
HGNC Approved Gene Symbol: DIDO1
Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38) : 20:62,877,743-62,937,904 (from NCBI)
By sequencing clones obtained from a size-fractionated human brain cDNA library, Nagase et al. (1997) cloned a partial DIDO1 cDNA, which they designated KIAA0333. The deduced protein contains a motif associated with nucleotide management. RT-PCR detected highest DIDO1 expression in placenta, followed by thymus and kidney. Lower expression was detected in all other tissues examined except skeletal muscle.
By differential-display PCR in pre-B cells undergoing apoptosis, Garcia-Domingo et al. (1999) identified a mouse gene that they referred to as Dio1 for 'death inducer-obliterator-1.' The human DIO1 cDNA, cloned from a fetal kidney cDNA library, encodes a 562-amino acid protein that exhibits 74% overall similarity to the mouse protein. The mouse and human proteins share a high degree of structural and compositional conservation. Mouse Dio1 mRNA and protein were present at very low levels in the cytoplasm. Once an appropriate apoptotic signal was detected, the protein translocated to the nucleus, and upregulation was observed at both transcript and protein levels. When overexpressed, it induced apoptosis in cell lines growing in vitro, which was prevented by blocking caspase activity.
Garcia-Domingo et al. (2003) found that mouse Dio1 forms oligomers. Western blot analysis detected triplet banding of Dio1. Two of 3 isoforms were phosphorylated on serine and threonine, but phosphatase treatment did not result in loss of multiple bands.
By Northern blot analysis, database analysis, and 3-prime RACE, Futterer et al. (2005) cloned 3 DIDO1 transcripts, which they called DIDO1, DIDO2, and DIDO3. The DIDO1 transcript was identified as the previously reported DIO1. The DIDO2 transcript was identified as the full-length clone of KIAA0333. In mouse, the Dido1, Dido2, and Dido3 transcripts encode proteins of 614, 1,183, and 2,256 amino acids, respectively. The 3 isoforms of the respective mouse and human DIDO1 genes are identical at the N-terminal end, which includes an N-terminal glutamine-rich region, an acidic region, a bipartite nuclear localization signal, and 2 central zinc finger motifs. Following this common sequence, the DIDO1 isoform terminates in a lysine-rich region, and the DIDO2 and DIDO3 isoforms continue with a domain similar to a TFS2M domain. Also, the DIDO3 isoform contains an additional long C-terminal domain. Immunolocalization of mouse cDNAs expressed in human embryonic kidney cells detected the Dido1 isoform in the cytosol, whereas both the Dido2 and Dido3 isoforms were detected in the nucleus.
The developing limb is one of the best-suited model systems for the study of apoptosis because fine tuning is required between cell proliferation and cell apoptosis to allow proper limb modeling, a process subject to intervention without endangering embryo viability. The DIO1 protein is expressed in chicken limb interdigitating membranes during development. Garcia-Domingo et al. (1999) tested in vivo the effect of the DIO1 gene. DIO1 expression in distal proliferating mesodermal cells of the developing chicken limb bud prevented limb outgrowth, an effect that correlated with inhibition of mesodermal and ectodermal genes involved in limb outgrowth.
In healthy mouse fibroblasts and pre-B lymphocytic cells, Garcia-Domingo et al. (2003) found phosphorylated Dio1 localized predominantly to the cytoplasm. Induction of apoptosis by interleukin-3 (IL3; 147740) starvation, or Myc (190080) upregulation, but not p53 (TP53; 191170) upregulation, resulted in the translocation of Dio1 to the nucleus where it upregulated caspase-3 (600636) and caspase-9 (602234) expression and activity. Nuclear Dio1 was unphosphorylated. A Dio1 mutant without the nuclear localization signal did not translocate to the nucleus upon Il3 withdrawal, and cells expressing this mutant were resistant to caspase activation and protected from apoptosis.
Trachana et al. (2007) found that in HeLa cells both endogenous DIDO3 and transfected mouse Dido3 concentrated at the spindle poles early in mitosis, reaching a maximum later in mitosis. Neither the Dido1 or Dido2 isoforms associated with centrosomes or cytoskeletal elements.
Futterer et al. (2005) determined that the DIDO1 gene contains 16 exons. A noncanonical splice site is used to splice exons 6 and 7 in the DIDO2 isoform, and second noncanonical splice site is used to splice exons 15 and 16 in the DIDO3 isoform.
By radiation hybrid analysis, Nagase et al. (1997) mapped the DIDO1 gene to chromosome 20.
By karyotypic analysis and genomic sequence analysis, Futterer et al. (2005) mapped the DIDO1 gene to chromosome 20q13.33. They mapped the mouse Dido1 gene to a region of chromosome 2H4 that shares homology of synteny with human chromosome 20q13.33.
By gene targeting, Futterer et al. (2005) disrupted the 5-prime exons of the mouse Dido gene. Homozygous null mice did not express the Dido1 or Dido2 isoforms, but they did express an N-terminally truncated Dido3 isoform translated from a methionine downstream of the zinc finger domain. Mutant animals were born at mendelian frequencies and appeared grossly normal at 1 month of age; however, by 7 to 8 months of age, some Dido +/- and Dido -/- mice showed abnormalities in spleen, bone marrow, and peripheral blood. Lesions included various combinations of symptoms characteristic of myeloid dysplasia or myeloid proliferation, including abnormal levels of erythroid, granulocytic, or monocytic cells in spleen and/or bone marrow; large numbers of dysplastic cells in spleen and/or bone marrow; splenomegaly; decreased colony formation accompanied by increased cluster formation potential of cultured granulocyte-macrophage and erythroid progenitors; anemia; and monocytosis or granulocytosis in peripheral blood.
By gene targeting, Trachana et al. (2007) created mice that expressed an N-terminally truncated form of Dido3. In mouse embryonic fibroblasts, full-length Dido3 localized to centrosomes/spindle poles, but truncated Dido3 lost centrosome association, and its expression resulted in defects in chromosome alignment in the metaphase plate. Dido3 disruption led to supernumerary centrosomes, failure to maintain cellular mitotic arrest, and early degradation of the mitotic checkpoint protein, Bubr1 (BUB1B; 602860). These aberrations resulted in enhanced aneuploidy in Dido3 mutant cells.
Futterer, A., Campanero, M. R., Leonardo, E., Criado, L. M., Flores, J. M., Hernandez, J. M., San Miguel, J. F., Martinez-A, C. Dido gene expression alterations are implicated in the induction of hematological myeloid neoplasms. J. Clin. Invest. 115: 2351-2362, 2005. [PubMed: 16127461] [Full Text: https://doi.org/10.1172/JCI24177]
Garcia-Domingo, D., Leonardo, E., Grandien, A., Martinez, P., Albar, J. P., Izpisua-Belmonte, J. C., Martinez-A, A. DIO-1 is a gene involved in onset of apoptosis in vitro, whose misexpression disrupts limb development. Proc. Nat. Acad. Sci. 96: 7992-7997, 1999. [PubMed: 10393935] [Full Text: https://doi.org/10.1073/pnas.96.14.7992]
Garcia-Domingo, D., Ramirez, D., Gonzalez de Buitrago, G., Martinez-A, C. Death inducer-obliterator 1 triggers apoptosis after nuclear translocation and caspase upregulation. Molec. Cell. Biol. 23: 3216-3225, 2003. [PubMed: 12697821] [Full Text: https://doi.org/10.1128/MCB.23.9.3216-3225.2003]
Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]
Trachana, V., van Wely, K. H. M., Guerrero, A. A., Futterer, A., Martinez-A, C. Dido disruption leads to centrosome amplification and mitotic checkpoint defects compromising chromosome stability. Proc. Nat. Acad. Sci. 104: 2691-2696, 2007. [PubMed: 17299043] [Full Text: https://doi.org/10.1073/pnas.0611132104]