P73 coordinates with ?133p53 to promote DNA double-strand break repair.

ABSTRACT: Tumour repressor p53 isoform ?133p53 is a target gene of p53 and an antagonist of p53-mediated apoptotic activity. We recently demonstrated that ?133p53 promotes DNA double-strand break (DSB) repair by upregulating transcription of the repair genes RAD51, LIG4 and RAD52 in a p53-independent manner. However, ?133p53 lacks the transactivation 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 ?133p53 and p73 (a p53 family member) at 24?h post ?-irradiation (hpi). ?133p53 can form a complex with p73 upon ?-irradiation. The co-expression of ?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 ?133p53 act synergistically to promote the expression of RAD51, LIG4 and RAD52 by joining together to bind to region containing a ?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 ?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.

SUBMITTER: Gong H 

PROVIDER: S-EPMC5988805 | biostudies-other | 2018 Jun

REPOSITORIES: biostudies-other