Department of Systems Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA.
Department of Chemistry, Northwestern University, Evanston, IL 60208, USA.
Sci Adv. 2024 Oct 25;10(43):eadp2229. doi: 10.1126/sciadv.adp2229.
The master regulator of the DNA damage response, the transcription factor p53, orchestrates multiple downstream responses and coordinates repair processes. In response to double-strand DNA breaks, p53 exhibits pulses of expression, but how it achieves temporal coordination of downstream responses remains unclear. Here, we show that p53's posttranslational modification state is altered between its first and second pulses of expression. We show that acetylations at two sites, K373 and K382, were reduced in the second pulse, and these acetylations differentially affected p53 target genes, resulting in changes in gene expression programs over time. This interplay between dynamics and modification may offer a strategy for cellular hubs like p53 to temporally organize multiple processes in individual cells.
DNA 损伤反应的主要调节因子转录因子 p53 协调多种下游反应并协调修复过程。在响应双链 DNA 断裂时，p53 表现出表达的脉冲，但它如何实现下游反应的时间协调仍然不清楚。在这里，我们表明 p53 的翻译后修饰状态在其第一次和第二次表达脉冲之间发生改变。我们表明，在第二个脉冲中，两个位点 K373 和 K382 的乙酰化减少，这些乙酰化作用差异地影响 p53 靶基因，导致随着时间的推移基因表达程序发生变化。这种动力学和修饰之间的相互作用可能为 p53 等细胞枢纽提供一种策略，以在单个细胞中临时组织多个过程。
