TP53 and neoplasm: As shown initially for the test case of the DNA-contact mutant R273H and later by saturating mutagenesis, missense mutants of the p53 DBD, but not outside of it, exert a dominant-negative effect over the wild-type protein through the formation of mixed tetramers with weakened DNA-binding [45, 46], which drastically reduces the amount of fully active wild-type homotetramers in heterozygous cells to a level that may not be sufficient for efficient tumor suppression.