Δ246p53 is a new p53 isoform that responds to DNA damage and regulates tumour growth

Abstract

ABSTRACTp53is with little doubt one of the most powerful genes in our genome, as it makes growthvsarrest, repairvsreplacement, metabolismvsanabolism, lifevsdeath decisions in the cell. One wrong action and a healthy cell is lost or transforms into cancer. So it is not surprising thatp53is also one of the most tightly regulated and complex genes.p53alone encodes for more than 10 RNA variants and 15 different protein forms. Here we identify yet another p53 protein isoform of around 18 KDa that we named Δ246p53. Δ246p53 is translated from an alternative translation initiation site (TIS) in codon 246. TIS-246 is preceded by a strong Kozak sequence and seems to be conserved in vertebrates, from sea lamprey to humans. Δ246p53’s origin and expression in cells were confirmed by frameshift and start codon mutations as well as siRNA and an antisense oligo targeting TIS-246, which knocked-down Δ246p53 with little or no effect on full-length (FL) p53 protein levels. Δ246p53 was induced by DNA damage in several cell lines tested and triggered senescence and impaired tumour formation/growth in colony formation assays. Lastly, we show that Δ246p53 binds to FLp53 and affects the transactivation ofp21, a known senescence activator. Our results add a new piece to the centre of the p53 puzzle, a previously unreported inside regulator of p53, which in the future may help us better understand p53’s still mystifying role in senescence and ageing.