Hosted by Toshi Kawate

ADP-Ribosylation Promotes Liquid-Liquid Phase Separation

to Degrade Hypoxia-Inducible Factor and Suppress Tumorigenesis

Precisely controlling the activation of transcription factors is crucial for physiology. After a transcription factor is activated and carries out its transcriptional activity, it also needs to be properly deactivated. Here we report a novel deactivation mechanism of hypoxia-inducible factor 1 (HIF-1) and several other oncogenic transcription factors. HIF-1 promotes the transcription of an ADP-ribosyltransferase, TiPARP, which serves to deactivate HIF-1. Mechanistically, TiPARP forms distinct nuclear liquid-liquid phase separation or nuclear bodies in an ADP-ribosylation-dependent manner. A WWE domain in TiPARP recognizes ADP-ribose and is important for the phase separation. The TiPARP nuclear bodies recruit both HIF-1α and an E3 ubiquitin ligase HUWE1, which promotes the ubiquitination and degradation of HIF-1a. Similarly, TiPARP promotes the degradation of c-Myc and estrogen receptor. By suppressing HIF-1a and other oncogenic transcription factors, TiPARP exert strong antitumor effect both in cell culture and in mouse xenograft models. Our work reveals TiPARP as a novel negative feedback regulator for multiple oncogenic transcription factors, provides insights into the role of protein ADP-ribosylation in mediating phase separation, and suggests activating TiPARP as an anticancer strategy.