p53 is induced in p53^{25,26,53,54/+} embryos and Chd7-null cells. (A) Schematic of the p53^25,26,53,54 protein with L25Q, W26S, F53Q, and F54S mutations and structural domains indicated. (B) Model for how p53^25,26,53,54 may stabilize and activate wild-type p53 (denoted by p53⁺). Top Left: p53^25,26,53,54 mutations disrupt the p53-interaction with Mdm2, resulting in stabilized p53 protein. Top Right: p53 can form tetramers comprised of any combination of mutant and/or wild-type p53 proteins, which can result in homotetramers or heterotetramers. Bottom Left: p53^25,26,53,54 can bind to DNA but is transactivation-deficient. Bottom Right: p53^25,26,53,54 can interact with wild-type p53 in heterotetramers, disrupt the p53-interaction with Mdm2, and promote wild-type p53 to transactivate target genes. Shown is an example of the type of heterotetramer that can form, although other subunit compositions are possible. C) Chd7 loss induces p53 expression. One mechanism by which Chd7 loss could induce p53 expression is through loss of Chd7 binding to the p53 promoter, resulting in derepression of p53 expression.

p53^{25,26,53,54/+} embryos display phenotypes characteristic of CHARGE syndrome. Characteristics of CHARGE syndrome are considered major features, minor features, or other features, depending on the specificity to CHARGE and the utility of the feature for diagnosing CHARGE. The phenotypes contributing to the CHARGE acronym are shaded in gray. Phenotypes observed in p53^{25,26,53,54/+} embryos are indicated with a +. nd: not determined in p53^{25,26,53,54/+} embryos, due in part to mid-late gestational embryonic lethality.

p53 hyperactivity is associated with multiple syndromes. Syndromes associated with p53 hyperactivity identified using mouse models and human patient samples. The phenotypes observed in human patients and the most commonly mutated genes associated with each syndrome are noted. The genotypes of the mouse models are noted. Our work identifies p53 hyperactivity in CHARGE syndrome using 3 independent criteria: p53 mutation being sufficient to cause phenotypes of the syndrome in a mouse model, p53 accumulation and/or activation in CHARGE patient samples, and p53-deficiency being able to rescue phenotypes in Chd7-deficient mice.

Summary of mouse strains with different levels of p53 activity and associated phenotypes. Mouse strains manifesting varying levels of p53 stabilization and/or activity exhibit diverse phenotypes ranging from embryonic lethality to premature aging to increased tumor susceptibility. The phenotypes and the p53 status in each indicated mouse strain are described.