The Effect Of Different TP53R273Mutants On Cancer Cells

Mutation of the tumor suppressor TP53gene occurs in greater than halfof all human cancers. In addition to loss of tumor suppressor function ofwild-type (wt) p53, gain-of-function (GOF) mutations endow cancer cellswith more malignant properties. R273is a mutation hotspot with theR273H, R273C, and R273G variants occurring most commonly in patientsamples. To better understand the consequences of these R273mutationswe constructed cancer cell lines expressing p53R273H, R273C or R273Gand explored their characteristics. We found that R273H and R273C, butnot R273G, enhanced proliferation, invasion and drug resistance in vitro.Furthermore, breast cancer susceptibility protein1(BRCA1) wasup-regulated by mutant p53R273H and R273C in response to DNAdamage and repair. Transcriptional analysis of the p53-R273mutants byRNA-seq confirmed that the apoptosis pathway was less active in R273Hand R273C, compared to R273G. Molecular dynamics simulation furtherrevealed that p53-R273G binds more tightly to DNA than p53-R273H orp53-R273C. These findings indicate that mutation of p53at a single codonhas different effects, and likely clinical implications. R273H and R273C lead to a more aggressive phenotype than273G. These findings maycontribute to future diagnosis and therapy in p53mutant cancers.