biostudies-literatureLiebl MCDeutsche Forschungsgemeinschaft2759-2776https://www.ebi.ac.uk/biostudies/studies/S-EPMC7969023biostudies-literatureUnknown49(5)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 celNucleic acids researchDAZAP2 acts as specifier of the p53 response to DNA damage.PMC7969023SFB 1361SFB 1036Abdeen SKRaddatz GLiebl MCBecker HAqeilan RIMoehlenbrink JHofmann TGLyko FfalseDAZAP2 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 cel2021-01-01T00:00:00Z2021 Mar2026-05-01T17:28:48.87Z2024-11-13T06:29:03.4ZS-EPMC79690233359131010.1093/nar/gkab084