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

Lu Zhang, Ji Cao, Longying Dong, Hening Lin

Proceedings of the National Academy of Sciences of the United States of America 2020 Jun 16

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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-1α and an E3 ubiquitin ligase HUWE1, which promotes the ubiquitination and degradation of HIF-1α. Similarly, TiPARP promotes the degradation of c-Myc and estrogen receptor. By suppressing HIF-1α 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. Copyright © 2020 the Author(s). Published by PNAS.

Citation

Lu Zhang, Ji Cao, Longying Dong, Hening Lin. TiPARP forms nuclear condensates to degrade HIF-1α and suppress tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America. 2020 Jun 16;117(24):13447-13456