期刊
NUCLEIC ACIDS RESEARCH
卷 49, 期 5, 页码 2759-2776出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab084
关键词
-
资金
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [201348542, 393547839, SFB 1036, SFB 1361]
- Deutsche Forschungsgemeinschaft [SFB 1361]
DAZAP2 is identified as a novel regulator of the DNA damage-induced p53 response, controlling cancer cell chemosensitivity through interaction with HIPK2 and p53 to modulate gene expression.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据