New Δ246p53 isoform responds to DNA damage to enhance p53 functions in senescence and tumour suppression

Abstract

p53 is with little doubt one of the most powerful genes in our genome, as it makes growth vs arrest, repair vs replacement, metabolism vs anabolism, life vs death decisions in the cell. An alteration or malfunction in p53 may lead to cancer or premature ageing. So, it is not surprising that p53 is also one of the most complex and tightly regulated genes. p53 alone encodes for at least 10 RNA variants and 12 widely accepted protein forms. Here we identify one new p53 protein isoform of around 18 kDa that we termed {Delta}246p53. {Delta}246p53 is translated from an alternative translation initiation site (TIS) in codon 246. TIS-246 is preceded by a strong Kozak sequence and appears conserved in vertebrates, from sea lamprey to humans. {Delta}246p53's origin and expression in cells were confirmed by frameshift and start codon mutations as well as siRNAs and an antisense oligo targeting TIS-246, which knocked-down {Delta}246p53 with little or no effect on full-length (FL) p53 protein levels. {Delta}246p53 was induced by DNA damage in several cancer and non-cancer cell lines and triggered senescence and impaired tumour formation/growth in colony formation assays. Lastly, we show that {Delta}246p53 inhibits Hdm2 expression and activates p21, a known senescence activator gene, through FLp53-dependent and -independent mechanisms, respectively. Our results add yet another regulated and naturally occurring factor to the list of p53 players, with specific roles in p53 activation and senescence. Further studies on {Delta}246p53's regulation and mode of action may help us better understand p53's still mystifying functions in senescence and ageing.