DAZAP2 acts as specifier of the p53 response to DNA damage.

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.
Mesh Terms:
Animals, Antineoplastic Agents, Carrier Proteins, Cell Line, Tumor, Cell Nucleus, Cells, Cultured, DNA Damage, Gene Expression Regulation, Mice, Nuclear Proteins, Promoter Regions, Genetic, Protein-Serine-Threonine Kinases, RNA-Binding Proteins, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases
Nucleic Acids Res
Date: Dec. 18, 2020
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