TiPARP forms nuclear condensates to degrade HIF-1? and suppress tumorigenesis.

ABSTRACT: 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 deactivation mechanism of 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 condensates or nuclear bodies in an ADP ribosylation-dependent manner. The TiPARP nuclear bodies recruit both HIF-1? and an E3 ubiquitin ligase HUWE1, which promotes the ubiquitination and degradation of HIF-1?. Similarly, TiPARP promotes the degradation of c-Myc and estrogen receptor. By suppressing HIF-1? and other oncogenic transcription factors, TiPARP exerts strong antitumor effects both in cell culture and in mouse xenograft models. Our work reveals TiPARP as a negative-feedback regulator for multiple oncogenic transcription factors, provides insights into the functions of protein ADP-ribosylation, and suggests activating TiPARP as an anticancer strategy.

SUBMITTER: Zhang L 

PROVIDER: S-EPMC7306777 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature