Identification of an E3 ligase that targets the catalytic subunit of RNA polymerase I upon transcription stress

Stephanie Pitts, Hester Liu, Adel Ibrahim, Amit Garg, Catarina Mendes Felgueira, Asma Begum, Wenjun Fan, Selina Teh, Jin-Yih Low, Brittany Ford, David A. Schneider, Ronald Hay, Marikki Laiho (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
6 Downloads (Pure)

Abstract

RNA Polymerase I (Pol I) synthesizes rRNA, which is the first and rate-limiting step in ribosome biogenesis. Factors governing the stability of the polymerase complex are not known. Previous studies characterizing Pol I inhibitor BMH-21 revealed a transcriptional stress-dependent pathway for degradation of the largest subunit of Pol I, RPA194. To identify the E3 ligase(s) involved, we conducted a cell-based RNAi screen for ubiquitin pathway genes. We establish Skp–Cullin–F-box protein complex F-box protein FBXL14 as an E3 ligase for RPA194. We show that FBXL14 binds to RPA194 and mediates RPA194 ubiquitination and degradation in cancer cells treated with BMH-21. Mutation analysis in yeast identified lysines 1150, 1153, and 1156 on Rpa190 relevant for the protein degradation. These results reveal the regulated turnover of Pol I, showing that the stability of the catalytic subunit is controlled by the F-box protein FBXL14 in response to transcription stress.

Original languageEnglish
Article number102690
Number of pages18
JournalJournal of Biological Chemistry
Volume298
Issue number12
Early online date10 Nov 2022
DOIs
Publication statusPublished - Dec 2022

Keywords

  • transcription
  • ubiquitin
  • proteasome
  • small molecule
  • cancer

Fingerprint

Dive into the research topics of 'Identification of an E3 ligase that targets the catalytic subunit of RNA polymerase I upon transcription stress'. Together they form a unique fingerprint.

Cite this