Parp7 generates an ADP-ribosyl degron that controls negative feedback of androgen signaling

作者：Krzysztof Wierbiłowicz, Chunsong Yang, Ahmed Almaghasilah, Patryk A. Wesołowski, Philipp Pracht, Natalia M. Dworak, Jack Masur, Sven Wijngaarden, Dmitri V. Filippov, David J. Wales, Joshua B. Kelley, Aakrosh Ratan, Bryce M. Paschal · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.12.21.629908 · 研究领域：PARP inhibition in cancer therapy

Abstract The androgen receptor (AR) tranduces the effects of circulating and tumor-derived androgens to the nucleus through ligand-induced changes in protein conformation, localization, and engagement with chromatin binding sites. Understanding these events and their integration with signal transduction is critical for defining how AR drives prostate cancer and unveiling pathway features that are amenable to therapeutic intervention. Here, we describe a novel post-transcriptional mechanism that controls AR protein levels on chromatin and associated gene output which is based on a highly selective, inducible degradation mechanism. We find that the mono-ADP-ribosyltransferase PARP7 generates an ADP-ribosyl degron on a single cysteine within the DNA binding domain of AR, which is then recognized by the ADP- ribose reader domain in the ubiquitin E3 ligase DTX2 and degraded by the proteasome. Mathematical modeling of the pathway suggested that PARP7 ADP-ribosylates chromatin-bound AR, a prediction that was validated in cells using an AR mutant that undergoes nuclear import but fails to bind DNA. Lysine- independent, non-conventional ubiquitin conjugation to ADP-ribosyl-cysteine and AR degradation by the proteasome forms the basis of a negative feedback loop that regulates specific modules of AR target genes. Our data expand the repertoire of mono-ADP-ribosyltransferase enzymes to include gene regulation based on highly selective protein degradation. One Sentence Summary PARP7 mono...