Ribosome ADP-ribosylation inhibits translation and maintains proteostasis in cancers

Sridevi Challa, Beman R. Khulpateea, Tulip Nandu, Cristel V. Camacho, Keun W. Ryu, Hao Chen, Yan Peng, Jayanthi S Lea, William L Kraus

Research output: Contribution to journalArticlepeer-review

Abstract

Defects in translation lead to changes in the expression of proteins that can serve as drivers of cancer formation. Here, we show that cytosolic NAD+ synthesis plays an essential role in ovarian cancer by regulating translation and maintaining protein homeostasis. Expression of NMNAT-2, a cytosolic NAD+ synthase, is highly upregulated in ovarian cancers. NMNAT-2 supports the catalytic activity of the mono(ADP-ribosyl) transferase (MART) PARP-16, which mono(ADP-ribosyl)ates (MARylates) ribosomal proteins. Depletion of NMNAT-2 or PARP-16 leads to inhibition of MARylation, increased polysome association and enhanced translation of specific mRNAs, aggregation of their translated protein products, and reduced growth of ovarian cancer cells. Furthermore, MARylation of the ribosomal proteins, such as RPL24 and RPS6, inhibits polysome assembly by stabilizing eIF6 binding to ribosomes. Collectively, our results demonstrate that ribosome MARylation promotes protein homeostasis in cancers by fine-tuning the levels of protein synthesis and preventing toxic protein aggregation.

Original languageEnglish (US)
Pages (from-to)4531-4546.e26
JournalCell
Volume184
Issue number17
DOIs
StatePublished - Aug 19 2021

Keywords

  • ADP-ribosylation
  • cancer
  • MARylation
  • mono(ADP-ribose)
  • mono(ADP-ribosyl)ation
  • mRNA translation
  • NAD
  • NAD sensor
  • NAD synthesis
  • NMNAT-2
  • ovarian cancer
  • PARP-16
  • protein aggregation
  • protein synthesis
  • ribosomes
  • translation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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