p73 coordinates with Delta 133p53 to promote DNA double-strand break repair

摘要

Tumour repressor p53 isoform Delta 133p53 is a target gene of p53 and an antagonist of p53-mediated apoptotic activity. We recently demonstrated that Delta 133p53 promotes DNA double-strand break (DSB) repair by upregulating transcription of the repair genes RADS1, LIG4 and RAD52 in a p53-independent manner. However, Delta 133p53 lacks the trans activation domain of full-length p53, and the mechanism by which it exerts transcriptional activity independently of full-length p53 remains unclear. In this report, we describe the accumulation of high levels of both Delta 133p53 and p73 (a p53 family member) at 24 h post gamma-irradiation (hpi). Delta 133p53 can form a complex with p73 upon gamma-irradiation. The co-expression of Delta 133p53 and p73, but not either protein alone, can significantly promote DNA DSB repair mechanisms, including homologous recombination (HR), non-homologous end joining (NHEJ) and single-strand annealing (SSA). p73 and Delta 133p53 act synergistically to promote the expression of RADS1, LIG4 and RAD52 by joining together to bind to region containing a Delta 133p53-responsive element (RE) and a p73-RE in the promoters of all three repair genes. In addition to its accumulation at 24 hpi, p73 protein expression also peaks at 4 hpi. The depletion of p73 not only reduces early-stage apoptotic frequency (4-6 hpi), but also significantly increases later-stage DNA DSB accumulation (48 hpi), leading to cell cycle arrest in the G2 phase and, ultimately, cell senescence. In summary, the apoptotic regulator p73 also coordinates with Delta 133p53 to promote DNA DSB repair, and the loss of function of p73 in DNA DSB repair may underlie spontaneous and carcinogen-induced tumorigenesis in p73 knockout mice.