Variation at the R181 Residue of p53 Confers Loss of p53 DNA Binding Cooperativity with the Retention of Mitochondria-Associated Apoptosis.

The p53 tumor suppressor binds DNA cooperatively as a tetramer, mediated by salt-bridge interactions between p53 residues E180 and R181 from 2 different p53 monomers. Variants at the R181 residue are one of the most identified TP53 pathogenic variants by germline genetic testing. We show that families with TP53 p.R181H and p.R181C variants have an attenuated cancer risk phenotype compared with patients with hotspot dominant-negative loss-of-function TP53 variants. Despite this phenotype, we find that p53 R181H and R181C variants have significantly reduced ability to bind to p53 promoter/enhancer target sequences and transactivate p53 target genes, similar to null variants. However, p53 R181H and R181C retain wild-type (WT) p53 structure and tetramerization. In addition, R181-mutant cells undergo apoptosis through WT p53 activity at the mitochondria. These results suggest that retention of transcription-independent p53 tumor suppressor function results in a reduced penetrance cancer risk syndrome in humans. IMPLICATIONS: We report the first separation of function DNA-binding domain p53 mutation that results in retention of transcription-independent p53 functions despite loss of p53 transactivation activity, resulting in a reduced penetrance phenotype.