TAp63γ enhances nucleotide excision repair through transcriptional regulation of DNA repair genes.

p63 and p73, two p53 family members, play crucial roles in development and tumor suppression. p63 and p73 have multiple isoforms, which have similar or distinct biological functions. Transactivation (TA) isoforms of p63 and p73 have high similarity with p53 and often have biological functions similar to p53. p53 plays an important role in nucleotide excision repair (NER) through transcriptional regulation of target genes involved in NER, including DDB2, XPC and GADD45. To investigate whether TAp63 and TAp73 play a similar role in NER, Saos2 cells with inducible expression of specific isoforms of TAp63 and TAp73, including TAp63α/β/γ and TAp73α/β/γ isoforms, were employed. Overexpression of TAp63γ significantly enhances NER of ultraviolet (UV)-induced DNA damage, including cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts, and enhances cell survival after UV irradiation in Soas2 cells. The enhancement of NER of UV-induced DNA damage by TAp63γ was also confirmed in H1299 cells with overexpression of TAp63γ. Consistently, knockdown of endogenous TAp63 decreases NER of UV-induced DNA damage in H1299 cells. TAp63α/β and TAp73α/β/γ isoforms do not have a clear effect on NER in Saos2 or H1299 cells. TAp63γ overexpression clearly induces the expression of DDB2, XPC and GADD45 at both RNA and protein levels. Furthermore, luciferase reporter assays show that TAp63γ transcriptionally activates DDB2, XPC and GADD45 genes through the regulation of the p53 binding elements in these genes. These results demonstrate that TAp63γ enhances NER to remove UV-induced DNA damage and maintain genomic stability through transcriptional induction of a set of NER proteins, which provides an additional important mechanism that contributes to the function of TAp63 in tumor suppression.