The gadd45 family of genes encodes for small (18kd), evolutionarily conserved proteins that are highly homologous to each other (55%–57% overall identity at the amino acid level), are highly acidic, and are primarily, but not exclusively, localized within the cell nucleus. The Gadd45 proteins stand at the crossroad of the cell fates by controlling the balance between cell (DNA) repair, eliminating (apoptosis) or preventing the expansion of potentially dangerous cells (cell cycle arrest, cellular senescence), and maintaining the stem cell pool.
The genotoxic stress of various natures could induce the transcriptional activity of Gadd45 genes, thus evoking Gadd45-mediated DNA repair. Several tumor suppressors involved in DNA repair and the FOXO transcription factors are particularly important in linking the stressful signals with Gadd45 repair activity. It is important to stress that since Gadd45 proteins are non-enzymatic, all their actions are realized through the interactions with either their protein partners or modulation of DNA/RNA accessibility to other proteins. One of the central DNA damage sensors – p53, a tumor suppressor protein which regulates cell cycle, DNA repair and apoptosis, is involved in the genotoxic stress-induced upregulation of Gadd45α. supporting the role of p53 in the regulation of Gadd45 expression is that the Gadd45-mediated cell cycle arrest is not observed in the Li-Fraumeni fibroblast culture bearing p53 gene mutation. Gadd45 is essential for a DNA damage-induced G2/M cell cycle arrest in both human and mouse fibroblasts. Microinjection of the Gadd45α expression vector into human primary fibroblasts arrests the cells in G2/M phase.
But Gadd45 proteins play dual role in apoptosis and cell survivalIn the case of irreparable damage, Gadd45 proteins exert a pro-apoptotic function. For example, the Gadd45 proteins mediate the endoplasmic reticulum stress-induced apoptosis in mouse liver cells. Another example includes the ectopic expression of Gadd45 in human leukemic cells or in mouse hepatocytes, which triggers apoptosis via the TGFβ/MEKK4/p38/JNK pathway, whereas blockage of the Gadd45βexpression suppresses the apoptosis induced by TGFβ. Gadd45 family members play an important role in cell differentiation, both during embryonic development and in the mature organism. Moreover, there is evidence that the expression of Gadd45 members may be cell type-specific. In many cases, the cell differentiation is preceded by cell cycle arrest in G1 phase and is consistently accompanied by an increased expression of Gadd45 proteins. For example, Gadd45γ is a primary transcription target of Ascl1, a transcription factor involved in neuronal differentiation.