DeltaNp63 alpha is an epithelial progenitor cell marker that maintains epidermal stem cell self-renewal capacity. Previous studies revealed that UV-damage induced p53 phosphorylation is confined to DeltaNp63 alpha-positive cells in the basal layer of human epithelium.

We now report that phosphorylation of the p53 tumour suppressor is positively regulated by DeltaNp63 alpha in immortalised human keratinocytes. DeltaNp63 alpha depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of DeltaNp63 alpha in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation. We show that ATM is a direct DeltaNp63 alpha transcriptional target and that the DeltaNp63 alpha response element localizes to the ATM promoter CCAAT sequence. Structure-function analysis revealed that the DeltaNp63 alpha-specific TA2 transactivation domain mediates ATM transcription in coordination with the DNA binding and SAM domains.

Germline p63 point mutations are associated with a range of ectodermal developmental disorders, and targeted p63 deletion in the skin causes premature ageing. The DeltaNp63 alpha-ATM-p53 damage-response pathway may therefore function in epithelial development, carcinogenesis and the ageing processes.

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