p73 coordinates with Δ133p53 to promote DNA double-strand break repair

Abstract

Tumour repressor p53 isoform Δ133p53 is a target gene of p53 and an antagonist of p53-mediated apoptotic activity. We recently demonstrated that Δ133p53 promotes DNA double-strand break (DSB) repair by upregulating transcription of the repair genes RAD51, LIG4 and RAD52 in a p53-independent manner. However, Δ133p53 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 Δ133p53 and p73 (a p53 family member) at 24 h post γ-irradiation (hpi). Δ133p53 can form a complex with p73 upon γ-irradiation. The co-expression of Δ133p53 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 Δ133p53 act synergistically to promote the expression of RAD51, LIG4 and RAD52 by joining together to bind to region containing a Δ133p53-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 Δ133p53 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.

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

“…In the present study, we report that the AMPK‐Mfn1 pathway is closely regulated by resveratrol . This finding provides an easy and effective approach to activate protective the AMPK‐Mfn1 pathway in the setting of cerebral IR injury …”

“…74,75 This finding provides an easy and effective approach to activate protective the AMPK-Mfn1 pathway in the setting of cerebral IR injury. 76…”

Δ133p53 decreases the chemosensitivity of carcinoma cell line H1299

“…Δ133p53 works together with the p53 gene family member p73 to join the promoters of all three repair genes Ligase4, Rad51, and Impact of Δ133p53 on the chemosensitivity K. Liu and J. Lin Rad52. Δ133p53, which cooperates with p73, acts synergistically to promote the expression of Rad51, Rad52, and Ligase4 and the repair of damaged DNA in various cancer cells Gong et al, , 2018. In this study, Δ133p53 reduced the sensitivity of H1299 to the chemotherapeutic drugs, due to which DNA of the cell line H1299 was injured.…”

“…Δ133p53 works together with the p53 gene family member p73 to join the promoters of all three repair genes Ligase4, Rad51, and Rad52. Δ133p53, which cooperates with p73, acts synergistically to promote the expression of Rad51, Rad52, and Ligase4 and the repair of damaged DNA in various cancer cells (Gong and Chen, ; Gong et al, , ).…”

Conformational stability and dynamics of the cancer‐associated isoform Δ133p53β are modulated by p53 peptides and p53‐specific DNA

“…Gong et al (74) found that D133p53 binds to DNp63 and utilizes its TA domain to promote glycolytic metabolism, leading to cancer cell proliferation. Additionally, p73 and D133p53 act synergistically to promote the expression of RAD51, LIG4, and RAD52 by binding to a region containing a D133p53-responsive element and a p73-responsive element in the promoters of all 3 DNA double-strand break repair genes (75). Figure 9.…”