The Cytidine Deaminase APOBEC3 Family Is Subject to Transcriptional Regulation by p53.

The APOBEC3 (A3) family of proteins are DNA cytidine deaminases that act as sentinels in the innate immune response against retroviral infections and are responsive to IFN. Recently, a few genes were identified as potent enzymatic sources of mutations in several human cancers. Using human cancer cells and lymphocytes, we show that under stress conditions and immune challenges, all genes are direct transcriptional targets of the tumor suppressor p53. Although the expression of most genes (including and ) was stimulated by the activation of p53, treatment with the DNA-damaging agent doxorubicin or the p53 stabilizer Nutlin led to repression of the gene. Furthermore, p53 could enhance IFN type-I induction of genes. Interestingly, overexpression of a group of tumor-associated p53 mutants in -null cancer cells promoted expression. These findings establish that the "guardian of the genome" role ascribed to p53 also extends to a unique component of the immune system, the genes, thereby integrating human immune and chromosomal stress responses into an A3/p53 immune axis. Activated p53 can integrate chromosomal stresses and immune responses through its influence on expression of genes, which are key components of the innate immune system that also influence genomic stability. .