Alternative titles; symbols
HGNC Approved Gene Symbol: GADD45A
Cytogenetic location: 1p31.3 Genomic coordinates (GRCh38): 1:67,685,201-67,688,334 (from NCBI)
Ionizing radiation can induce specific genes in mammalian and other eukaryotic cells. Two such genes, often referred to as GADD45 and GADD153 (126337), are strongly and coordinately induced by ultraviolet radiation and alkylating agents in human and hamster cells. (These genes are designated GADD for 'growth arrest- and DNA damage-inducible.') Papathanasiou et al. (1991) found that GADD45 but not GADD153 is strongly induced by x-rays in human cells. No induction was seen after treatment with a known activator of protein kinase C (see PKCA, 176960). Therefore, GADD45 is the only known x-ray responsive gene whose induction is not mediated by PKC. Sequence analysis of human and hamster cDNA clones demonstrated that the gene has been highly conserved and encodes a novel 165-amino acid polypeptide that is 96% identical in the 2 species. In cell lines from 4 patients with ataxia-telangiectasia (208900), Papathanasiou et al. (1991) demonstrated that induction by x-ray of GADD45 mRNA was reduced in comparison to the normal.
The stress-responsive p38 (see MAPK14; 600289) and JNK (see MAPK8; 601158) mitogen-activated protein kinase (MAPK) pathways regulate cell cycle and apoptosis. A human MAP3K, MTK1 (MAP3K4; 602425), mediates activation of both p38 and JNK in response to environmental stresses. By screening a placenta cDNA library using a yeast 2-hybrid method, Takekawa and Saito (1998) isolated cDNAs encoding 3 related proteins, GADD45A, GADD45-beta (GADD45B; 604948), and GADD45-gamma (GADD45G; 604949), that bound to an N-terminal domain of MTK1. GADD45A, GADD45B, and GADD45G share 55 to 58% amino acid identity. These proteins activated MTK1 kinase activity, both in vivo and in vitro. All 3 GADD45-like genes were induced by environmental stresses, including methyl methanesulfonate, UV, and gamma irradiation. Expression of the GADD45-like genes induced p38/JNK activation and apoptosis, which could be partially suppressed by coexpression of a dominant inhibitory MTK1 mutant protein. Northern blot analysis detected moderate expression of a 1.4-kb GADD45A transcript in heart, skeletal muscle, and kidney, with little or no expression in brain, placenta, lung, liver, and pancreas. Takekawa and Saito (1998) proposed that the GADD45-like proteins mediate activation of the p38/JNK pathway, via MTK1, in response to environmental stresses.
Smith et al. (1994) found that GADD45 binds to PCNA, or proliferating cell nuclear antigen (176740), a normal component of cyclin-dependent kinase complexes and a protein involved in DNA replication and repair. GADD45 stimulated DNA excision repair in vitro and inhibited entry of cells into S phase. These results established GADD45 as a link between the p53 (191170)-dependent cell cycle checkpoint and DNA repair.
Using antibodies against the recombinant protein, Carrier et al. (1994) demonstrated that GADD45 is predominantly a nuclear protein. Kearsey et al. (1995) also showed that GADD45 is a nuclear protein, widely expressed in normal tissues, particularly in quiescent cells. Using cell synchronization methods, they showed that GADD45 levels are highest in the G1 phase of the cell cycle, and are greatly reduced during S phase. They presented evidence that GADD45 directly interacts with p21(Cip1), a cell cycle inhibitor (116899). Interactions also with PCNA are probably important for the modulation of cell cycles and for the inhibition of DNA replication.
Using differential expression and immunohistochemical analyses of benign nevi and melanomas of different levels, Korabiowska et al. (1997) observed p53 negativity and high expression of GADD34 (PPP1R15A; 611048), GADD45, and GADD153 in all nevi. However, in melanomas, p53 expression increased and GADD expression decreased with the Clark level of melanoma thickness. Patient survival time correlated negatively with p53 positivity and positively with GADD45 and GADD153 expression. Korabiowska et al. (1997) concluded that GADD proteins play an important role in the malignant transformation of nevus to melanoma.
Tran et al. (2002) demonstrated that mammalian FOXO3A (602681) functions at the G2-M checkpoint in the cell cycle and triggers the repair of damaged DNA. By gene array analysis, FOXO3A was found to modulate the expression of several genes that regulate the cellular response to stress at the G2-M checkpoint. The growth arrest and DNA damage response gene GADD45A appeared to be a direct target of FOXO3A that mediates part of FOXO3A's effects on DNA repair. Tran et al. (2002) concluded that in mammals, FOXO3A regulates the resistance of cells to stress by inducing DNA repair and thereby may also affect organismal life span.
Bruemmer et al. (2003) presented evidence that PPARG (601487) ligands induce caspase-mediated apoptosis via GADD45 expression in human coronary artery vascular smooth muscle cells. Deletion analysis of the GADD45 promoter revealed a region between -234 and -81 bp proximal to the transcription start that contains an OCT1 (164175) element and is crucial for PPARG ligand-mediated induction of the GADD45 promoter. PPARG activation induced OCT1 protein expression and DNA binding and stimulated activity of a reporter plasmid driven by multiple OCT1 elements. Bruemmer et al. (2003) concluded that activation of PPARG can lead to apoptosis and growth arrest in vascular smooth muscle cells, at least in part, by inducing OCT1-mediated transcription of GADD45.
Lal et al. (2006) found AUF1 (HNRNPD; 601324) and TIAR (TIAL1; 603413) interacted with the 3-prime UTR of GADD45A in HeLa cells. AUF1 reduced GADD45A mRNA stability, whereas TIAR inhibited GADD45A translation. After genotoxic stress, AUF1 and TIAR dissociated from GADD45A mRNA, thereby increasing GADD45A mRNA stability and translation. Lal et al. (2006) concluded that posttranscriptional derepression of GADD45A contributes to its upregulation after DNA damage.
Barreto et al. (2007) showed that GADD45A, a nuclear protein involved in maintenance of genomic stability, DNA repair, and suppression of cell growth, has a key role in active DNA demethylation. GADD45A overexpression activates methylation-silenced reporter plasmids and promotes global DNA demethylation. GADD45A knockdown silences gene expression and leads to DNA hypermethylation. During active demethylation of oct4 (164177) in Xenopus laevis oocytes, GADD45A is specifically recruited to the site of demethylation. Active demethylation occurs by DNA repair, and GADD45A interacts with and requires the DNA repair endonuclease XPG (133530). Barreto et al. (2007) concluded that GADD45A relieves epigenetic gene silencing by promoting DNA repair, which erases methylation marks.
By analysis of human/rodent somatic cell hybrids, Papathanasiou et al. (1991) demonstrated that the GADD45 gene is located on 1p34-p12.
Hollander et al. (1999) reported that Gadd45a-null mice generated by gene targeting exhibited several phenotypes characteristic of mice deficient in p53, including genomic instability, increased radiation carcinogenesis and a low frequency of exencephaly. Genomic instability was exemplified by aneuploidy, chromosome aberrations, gene amplification, and centrosome amplification, and was accompanied by abnormalities in mitosis, cytokinesis, and growth control. Unequal segregation of chromosomes due to multiple spindle poles during mitosis occurred in several Gadd45a -/- cell lineages and may contribute to the aneuploidy. The results indicated that Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability.
Salvador et al. (2002) showed that GADD45A is a negative regulator of T-cell proliferation because, compared with wildtype cells, T cells, but not B cells, from Gadd45a-deficient mice had a lower threshold of activation and proliferated to a greater extent. The mutant mice were also prone to a systemic lupus erythematosus (152700)-like condition characterized by high titers of anti-dsDNA, anti-ssDNA, and antihistone antibodies, severe hematologic disorders, autoimmune glomerulonephritis, and premature death. In mice lacking both Gadd45a and p21, the development of autoimmunity was greatly accelerated.
Mouse embryonic fibroblasts carrying targeted deletion of exon 11 of the Brca1 gene (113705) or a Gadd45a null mutation suffer centrosome amplification. Wang et al. (2004) found that mouse embryos carrying both mutations were exencephalic and exhibited a high incidence of apoptosis accompanied by altered levels of Bax (600040), Bcl2 (151430), and p53. They concluded that BRCA1 and GADD45A have a synergistic role in regulating centrosome duplication and maintaining genome integrity.
Barreto, G., Schafer, A. Marhold, J., Stach, D., Swaminathan, S. K., Handa, V., Doderlein, G., Maltry, N., Wu, W., Lyko, F., Niehrs, C. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 445: 671-675, 2007. [PubMed: 17268471] [Full Text: https://doi.org/10.1038/nature05515]
Bruemmer, D., Yin, F., Liu, J., Berger, J. P., Sakai, T., Blaschke, F., Fleck, E., Van Herle, A. J., Forman, B. M., Law, R. E. Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor gamma in vascular smooth muscle cells. Circ. Res. 93: e38-e47, 2003. [PubMed: 12881480] [Full Text: https://doi.org/10.1161/01.RES.0000088344.15288.E6]
Carrier, F., Smith, M. L., Bae, I., Kilpatrick, K. E., Lansing, T. J., Chen, C.-Y., Engelstein, M., Friend, S. H., Henner, W. D., Gilmer, T. M., Kastan, M. B., Fornace, A. J., Jr. Characterization of human Gadd45, a p53-regulated protein. J. Biol. Chem. 269: 32672-32677, 1994. [PubMed: 7798274]
Hollander, M. C., Sheikh, M. S., Bulavin, D. V., Lundgren, K., Augeri-Henmueller, L., Shehee, R., Molinaro, T. A., Kim, K. E., Tolosa, E., Ashwell, J. D., Rosenberg, M. P., Zhan, Q., Fernandez-Salguero, P. M., Morgan, W. F., Deng, C.-X., Fornace, A. J., Jr. Genomic instability in Gadd45a-deficient mice. Nature Genet. 23: 176-184, 1999. [PubMed: 10508513] [Full Text: https://doi.org/10.1038/13802]
Kearsey, J. M., Coates, P. J., Prescott, A. R., Warbrick, E., Hall, P. A. Gadd45 is a nuclear cell cycle regulated protein which interacts with p21(Cip1). Oncogene 11: 1675-1683, 1995. [PubMed: 7478594]
Korabiowska, M., Betke, H., Kellner, S., Stachura, J., Schauer, A. Differential expression of growth arrest, DNA damage genes and tumour suppressor gene p53 in naevi and malignant melanomas. Anticancer Res. 17: 3697-3700, 1997. [PubMed: 9413226]
Lal, A., Abdelmohsen, K., Pullmann, R., Kawai, T., Galban, S., Yang, X., Brewer, G., Gorospe, M. Posttranscriptional derepression of GADD45-alpha by genotoxic stress. Molec. Cell 22: 117-128, 2006. [PubMed: 16600875] [Full Text: https://doi.org/10.1016/j.molcel.2006.03.016]
Papathanasiou, M. A., Kerr, N. C. K., Robbins, J. H., McBride, O. W., Alamo, I., Jr., Barrett, S. F., Hickson, I. D., Fornace, A. J., Jr. Induction by ionizing radiation of the GADD45 gene in cultured human cells: lack of mediation by protein kinase C. Molec. Cell. Biol. 11: 1009-1016, 1991. [PubMed: 1990262] [Full Text: https://doi.org/10.1128/mcb.11.2.1009-1016.1991]
Salvador, J. M., Hollander, M. C., Nguyen, A. T., Kopp, J. B., Barisoni, L., Moore, J. K., Ashwell, J. D., Fornace, A. J., Jr. Mice lacking the p53-effector gene Gadd45a develop a lupus-like syndrome. Immunity 16: 499-508, 2002. [PubMed: 11970874] [Full Text: https://doi.org/10.1016/s1074-7613(02)00302-3]
Smith, M. L., Chen, I.-T., Zhan, Q., Bae, I., Chen, C.-Y., Gilmer, T. M., Kastan, M. B., O'Connor, P. M., Fornace, A. J., Jr. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science 266: 1376-1380, 1994. [PubMed: 7973727] [Full Text: https://doi.org/10.1126/science.7973727]
Takekawa, M., Saito, H. A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 95: 521-530, 1998. [PubMed: 9827804] [Full Text: https://doi.org/10.1016/s0092-8674(00)81619-0]
Tran, H., Brunet, A., Grenier, J. M., Datta, S. R., Fornace, A. J., Jr., DiStefano, P. S., Chiang, L. W., Greenberg, M. E. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296: 530-534, 2002. [PubMed: 11964479] [Full Text: https://doi.org/10.1126/science.1068712]
Wang, X., Wang, R.-H., Li, W., Xu, X., Hollander, M. C., Fornace, A. J., Jr., Deng, C.-X. Genetic interactions between Brca1 and Gadd45a in centrosome duplication, genetic stability, and neural tube closure. J. Biol. Chem. 279: 29606-29614, 2004. [PubMed: 15123655] [Full Text: https://doi.org/10.1074/jbc.M312279200]