Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death

Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetram-ers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profi le and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochon-dria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein.

Automated summary

This study investigates the pathogenic mechanism of cancer susceptibility genes and finds that the p53(A347D) mutation leads to the inability of p53 to form tetramers, resulting in a hyperstable dimeric state and the inability to bind and activate most canonical p53 target genes, but possessing neomorphic functions. Cells with the p53(A347D) mutation have similar tumorigenic capabilities compared to cells without p53, but the mutation can induce metabolic reprogramming and severe mitochondrial network abnormalities, and can drive apoptotic cell death via mitochondrial association in the absence of transcriptional activity upon topoisomerase II inhibition.