GADD45A Research Reagents

GADD45A Background

The GADD45A gene was initially isolated from Chinese Hamster Ovarian (CHO) cells based on rapid induction under UV exposure ^[1]. Growth arrest and DNA-damage-inducible protein 45 alpha (GADD45α/GADD45A) is one of the GADD45 family proteins that act as stress sensors that regulate the response of mammalian cells to genotoxic/physiological stress and modulate tumor formation. GADD45A is widely expressed and predominantly localized in nucluse ^[2]. Interacting with multiple important cellular proteins, GADD45A is responsive to numerous agents implicated in DNA damage, apoptosis, cell cycle checkpoint control, cell injury, and other growth regulatory processes ^[3]. GADD45A has roles both in S-phase and G2/M arrest ^[4][5]. It inhibits DNA replication during the S phase by replacing PCNA from the cyclin D1 complex ^[4]. Similarly, GADD45A binds to Cdk1, blocking its interaction with cyclin B1, thus suppressing Cdk1 activity, stagnating the cell at the G2/M checkpoint, and inducing apoptosis ^[6]. GADD45A appears to negatively modulate the tumor suppressor CDKN1A (cyclin-dependent kinase inhibitor 1 a) expression in keratinocytes, permitting nucleotide excision repair (NER) after UV radiation ^[3]. p38 phosphorylates p53, upregulating downstream effector GADD45A, which is contrarily conducive to activate p53 via p38 ^[5]. The process establishes a positive feedback loop that is transient during genotoxic stress-induced growth arrest, and that is required during oncogene-induced permanent growth arrest ^[7]. Therefore, mice deleted the GADD45A gene exhibited genomic instability, increased carcinogenesis, and a low frequency of exencephaly after genotoxic stresses such as ionizing radiation (IR) and UV radiation, consistently with previous study results ^[8]. These results also indicated that GADD45A is one component of the p53 pathway that contributes to the maintenance of genomic stability ^[8]. Besides, GADD45A also has a role in DNA-demethylation to promote genome stability. The binding of GADD45A and ING1b is required for DNA demethylation of methylated reporter plasmids ^[9]. In many malignancies, GADD45A is down-regulation, which probably allows for the elusion of tumor cells from senescence and apoptosis. Novel approaches are, therefore, being developed to regulate GADD45A levels to combat malignancies.

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[2] Rosemary Siafakas A, Richardson DR. Growth arrest and DNA damage-45 alpha (GADD45alpha) [J]. Int J Biochem Cell Biol. 2009 May;41(5):986-9.
[3] Zhan Q. Gadd45a, a p53- and BRCA1-regulated stress protein, in cellular response to DNA damage [J]. Mutat Res. 2005 Jan 6; 569(1-2):133-43.
[4] Smith ML, Chen IT, et al. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen [J]. Science. 1994 Nov 25;266(5189):1376-80.
[5] Hollander MC, Fornace AJ. Genomic instability, centrosome amplification, cell cycle checkpoints and Gadd45a [J]. Oncogene. 2002;21:6228–33.
[6] Salvador JM, Brown-Clay JD, et al. Gadd45 in stress signaling, cell cycle control, and apoptosis [J]. Adv Exp Med Biol. 2013; 793:1-19.
[7] Bulavin DV, Kovalsky O, et al. Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of Gadd45a [J]. Mol Cell Biol. 2003;23:3859–71.
[8] Hollander MC, Sheikh MS, et al. Genomic instability in Gadd45a-deficient mice [J]. Nat Genet. 1999 Oct;23(2):176-84.
[9] Andrea Schäfer, Emil Karaulanov, et al. Ing1 functions in DNA demethylation by directing Gadd45a to H3K4me3 [J]. Genes & Dev. 2013. 27: 261-273.