p73 coordinates with Δ133p53 to promote DNA double-strand break repair.
p73 coordinates with Δ133p53 to promote DNA double-strand break repair.
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p73与Delta 133p53协调促进DNA双链断裂修复
DOI：
10.1038/s41418-018-0085-8
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发表时间：
2018-06
影响因子：
12.4
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Gong H;Zhang Y;Jiang K;Ye S;Chen S;Zhang Q;Peng J;Chen J
肿瘤抑制蛋白p53亚型Δ 133 p53是p53的靶基因，是p53介导的凋亡活性的拮抗剂。我们最近证明Δ 133 p53通过以p53非依赖性方式上调修复基因RAD 51、LIG 4和RAD 52的转录来促进DNA双链断裂（DSB）修复。然而，Δ 133 p53缺乏全长p53的反式激活结构域，并且其独立于全长p53发挥转录活性的机制仍不清楚。在本报告中，我们描述了γ射线照射后24小时（hpi）高水平的Δ 133 p53和p73（p53家族成员）的积累。γ射线照射后Δ 133 p53可与p73形成复合物。Δ 133 p53和p73的共表达（但单独的蛋白质都不能）可以显着促进DNA DSB修复机制，包括同源重组（HR）、非同源末端连接（NHEJ）和单链退火（SSA）。p73和Δ 133 p53协同作用，通过连接在一起以结合所有三个修复基因的启动子中含有Δ 133 p53-响应元件（RE）和p73-RE的区域来促进RAD 51、LIG 4和RAD 52的表达。除了其在24 hpi的积累外，p73蛋白表达也在4 hpi达到峰值。p73的耗尽不仅降低早期凋亡频率（4-6 hpi），而且显著增加晚期DNA DSB积累（48 hpi），导致细胞周期停滞在G2期，并最终导致细胞衰老。总之，凋亡调节因子p73也与Δ 133 p53协调促进DNA DSB修复，p73在DNA DSB修复中功能的丧失可能是p73敲除小鼠自发性和致癌物诱导的肿瘤发生的基础。
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.
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影响因子：
14.9
作者：
Christmann M;Kaina B
通讯作者：
Kaina B
影响因子：
16.6
作者：
Horikawa I;Fujita K;Jenkins LM;Hiyoshi Y;Mondal AM;Vojtesek B;Lane DP;Appella E;Harris CC
通讯作者：
Harris CC
影响因子：
16
作者：
Ciccia A;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
4.8
作者：
Flinterman, M;Guelen, L;Tavassoli, M
通讯作者：
Tavassoli, M
具有不同转录活性的两个新的P73剪接变体伽马和三角洲。
影响因子：
15.3
作者：
De Laurenzi, V;Costanzo, A;Barcaroli, D;Terrinoni, A;Falco, M;Annicchiarico-Petruzzelli, M;Levrero, M;Melino, G
通讯作者：
Melino, G