DAZAP2 controls cancer cell chemosensitivity by orchestrating the p53 response upon DNA damage

The tumor suppressors p53 and HIPK2 play a central role in cell fate decision-making upon DNA damage and regulate cancer cell chemosensitivity. Here we identify the adaptor protein Deleted in Azoospermia-associated protein 2 (DAZAP2) as a novel player in the DNA damage-induced p53 response. Knock-down or genetic deletion of DAZAP2 potentiates cancer cell chemosensitivity in vitro and in vivo. In unstressed cells, DAZAP2 stimulates HIPK2 ubiquitination and degradation through interaction with HIPK2 and the ubiquitin ligase SIAH1. After chemotherapeutic drug-induced DNA damage, DAZAP2 accumulates in the cell nucleus, which is regulated through site-specific phosphorylation by HIPK2. Nuclear DAZAP2 interacts with p53 response elements and specifies p53 target gene expression by modulating a select subset of p53 target genes. Mechanistically, DAZAP2 forms a complex with p53 and modulates target gene expression in association with HDAC1. Our findings identify DAZAP2 as a novel regulator of the p53 response and cancer cell chemosensitivity. Overall design: Whole transcriptome analysis to identify DAZAP2-regulated genes under physiological conditions or upon DNA damage. Briefly, HCT116 cells were either transfected with a siRNA targeting DAZAP2 or a control siRNA followed by treatment with either DMSO or 50 µM 5-FU for 24 h. 3 biological replicates per group were analyzed.