Institute of Toxicology, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany.
Division of Epigenetics, German Cancer Research Center (dkfz), Heidelberg, Germany.
Nucleic Acids Res. 2021 Mar 18;49(5):2759-2776. doi: 10.1093/nar/gkab084.
The DNA damage-responsive tumor suppressors p53 and HIPK2 are well established regulators of cell fate decision-making and regulate the cellular sensitivity to DNA-damaging drugs. Here, we identify Deleted in Azoospermia-associated protein 2 (DAZAP2), a small adaptor protein, as a novel regulator of HIPK2 and specifier of the DNA damage-induced p53 response. Knock-down or genetic deletion of DAZAP2 strongly potentiates cancer cell chemosensitivity both in cells and in vivo using a mouse tumour xenograft model. In unstressed cells, DAZAP2 stimulates HIPK2 polyubiquitination and degradation through interplay with the ubiquitin ligase SIAH1. Upon DNA damage, HIPK2 site-specifically phosphorylates DAZAP2, which terminates its HIPK2-degrading function and triggers its re-localization to the cell nucleus. Interestingly, nuclear DAZAP2 interacts with p53 and specifies target gene expression through modulating a defined subset of p53 target genes. Furthermore, our results suggest that DAZAP2 co-occupies p53 response elements to specify target gene expression. Collectively, our findings propose DAZAP2 as novel regulator of the DNA damage-induced p53 response that controls cancer cell chemosensitivity.
DNA 损伤反应性肿瘤抑制因子 p53 和 HIPK2 是细胞命运决策的公认调节剂，调节细胞对 DNA 损伤药物的敏感性。在这里，我们确定Deleted in Azoospermia-associated protein 2（DAZAP2），一种小衔接蛋白，作为 HIPK2 的新型调节剂和 DNA 损伤诱导的 p53 反应的指定因子。使用小鼠肿瘤异种移植模型，在细胞和体内，敲低或基因删除 DAZAP2 可显著增强癌细胞的化学敏感性。在未受应激的细胞中，DAZAP2 通过与泛素连接酶 SIAH1 的相互作用刺激 HIPK2 的多泛素化和降解。在 DNA 损伤后，HIPK2 特异性地磷酸化 DAZAP2，终止其 HIPK2 降解功能，并触发其重新定位到细胞核。有趣的是，核内 DAZAP2 与 p53 相互作用，并通过调节一组特定的 p53 靶基因来指定靶基因的表达。此外，我们的结果表明，DAZAP2 共同占据 p53 反应元件以指定靶基因的表达。总之，我们的研究结果提出了 DAZAP2 作为控制癌细胞化学敏感性的 DNA 损伤诱导的 p53 反应的新型调节剂。
Zotero 插件
