Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China.
Stem Cells. 2022 Nov 29;40(11):1008-1019. doi: 10.1093/stmcls/sxac058.
p53 plays a pivotal role in maintaining the genomic stability of mouse embryonic stem cells (mESCs) through transcriptionally activating and repressing target genes. However, how p53 recognizes its repressed targets remains largely unknown. Herein, we demonstrate that Sall4 negatively regulates DNA damage induced apoptosis (DIA) of mESCs through mediating p53 recruitment to enhancers of ESC-associated genes repressed by p53 from promoters of p53-activated genes. Upon DNA damage, Sall4 is transcriptionally repressed by p53 and plays an anti-apoptotic role without altering p53 activation. Moreover, Sall4 is identified as a novel p53-interacting partner. Consistently, Sall4 exerts its anti-apoptotic function in a p53-dependent manner. Intriguingly, Sall4 depletion not only promotes the transcriptional activation of several p53-regulated pro-apoptotic genes but also compromises p53-mediated repression of ESC master transcription factors in response to DNA damage. Mechanistically, Sall4 balances p53-binding affinity between p53-activated and -repressed genes through tethering p53 to ESC enhancers. In light of our study, Sall4 may contribute to tumorigenesis by antagonizing p53-mediated apoptosis.
p53 通过转录激活和抑制靶基因，在维持小鼠胚胎干细胞（mESCs）的基因组稳定性方面发挥着关键作用。然而，p53 如何识别其受抑制的靶标在很大程度上仍然未知。在此，我们证明 Sall4 通过介导 p53 招募到 p53 激活基因的启动子上受 p53 抑制的 ESC 相关基因的增强子，从而负调控 mESCs 的 DNA 损伤诱导的细胞凋亡（DIA）。在 DNA 损伤后，p53 转录抑制 Sall4 并发挥抗凋亡作用，而不改变 p53 的激活。此外，Sall4 被鉴定为一种新的 p53 相互作用伙伴。一致地，Sall4 以 p53 依赖的方式发挥其抗凋亡功能。有趣的是，Sall4 的耗竭不仅促进了几个 p53 调节的促凋亡基因的转录激活，而且还损害了 p53 介导的对 DNA 损伤的 ESC 主转录因子的抑制。在机制上，Sall4 通过将 p53 固定在 ESC 增强子上，平衡 p53 在 p53 激活和抑制基因之间的结合亲和力。鉴于我们的研究，Sall4 可能通过拮抗 p53 介导的细胞凋亡促进肿瘤发生。
