Significance and context
The tumor suppressor gene p53 has been referred to as the 'guardian of the genome'. Mutations in the p53 gene are found in many human tumours, and p53 loss is associated with diverse consequences including genomic instability, loss of cell-cycle checkpoint controls, increased carcinogenesis, decreased apoptosis, reduced DNA repair and a low frequency of exencephaly (a developmental brain defect). Many functions of p53 protein are related to its ability to regulate gene expression. Identified p53-regulated genes account for some of the p53 functions; for example, the p21/Cip1/Waf1 inhibitor of cyclin-dependent kinases regulates cell-cycle checkpoint control in G1 phase and bax regulates apoptosis (see Figure 1). The p53 effector genes involved in genomic instability are unknown, however. This is the first report to use a genetic approach to define a role for Gadd45a, an established p53-regulated gene, in genomic stability and growth control.
Figure 1. Examples of known p53 effector genes that have distinct cellular effects.
The authors generated mice with a disrupted Gadd45a gene using a standard homologous recombination approach. Most of the Gadd45a–/– mice were viable and fertile. The authors note a low frequency of exencephaly (8%), similar to that reported for p53–/– mice. Embryonic fibroblasts isolated from these mice exhibited features of cells lacking p53: they grew faster than wild-type cells, escaped senescence, and could be transformed with a single activated oncogene. Furthermore, these Gadd45a-deficient fibroblasts showed increased aneuploidy, chromosomal aberrations, centromere fusions, aberrant cytokinesis and centrosome amplifications. The Gadd45a-deficient mice were hypersensitive to γ-irradiation-induced carcinogenesis, whereas heterozygote mice were intermediate in sensitivity between deficient and wild-type animals. The knockout mice also displayed increased numbers of cells in the thymus without evidence of decreased apoptosis. Finally, the authors report reduced G2 checkpoint control following treatment with DNA-damaging agents (ultraviolet radiation and methyl methane sulphonate).
The authors note that other tumour suppressor genes, such as Brca1 and Brca2, also regulate Gadd45a expression, supporting the notion that Gadd45a has a broad role in surveillance of genome stability. They refer to Gadd45a as an 'alarm factor', alerting the cell to stress and cellular injury. They suggest that in the absence of Gadd45a defective cytokinesis, centromeric fusions and amplifications are likely to contribute to unbalanced chromosome segregation and subsequent aneuploidy.
Convincing evidence is provided here that distinct downstream effectors may account for different aspects of the pleiotropic phenotypes observed upon p53 mutation. Clearly, much work is now needed to investigate the mechanism by which the Gadd45 protein maintains genomic stability. Gadd45 has been reported to interact with PCNA, p21 and Cdc2 proteins, suggesting that it plays diverse roles in regulating genome stability and cell cycle control. The similarities between Gadd45a and p53 null mutation phenotypes will encourage researchers to investigate Gadd45a status in human tumours and to focus on this p53 effector in future anti-cancer drug intervention strategies.