Ribosome ADP-ribosylation inhibits translation and maintains proteostasis in cancers.

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.

• Authors: Sridevi Challa, Beman R Khulpateea, Tulip Nandu, Cristel V Camacho, Keun W Ryu, Hao Chen, Yan Peng, Jayanthi S Lea, W Lee Kraus
• Journal: Cell (Cell) Vol. 184 Issue 17 Pg. 4531-4546.e26 (08 19 2021) ISSN: 1097-4172 [Electronic] United States
• PMID: 34314702 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• 3' Untranslated Regions
• RNA, Messenger
• RNA, Small Interfering
• Ribosomal Proteins
• NAD
• PARP16 protein, human
• Poly(ADP-ribose) Polymerases
• NMNAT2 protein, human
• Nicotinamide-Nucleotide Adenylyltransferase

Topics

• 3' Untranslated Regions (genetics)
• ADP-Ribosylation
• Animals
• Base Sequence
• Cell Line, Tumor
• Cell Proliferation
• Endoplasmic Reticulum Stress
• Fallopian Tubes (metabolism)
• Female
• Humans
• Mice, Inbred NOD
• Mice, SCID
• NAD (metabolism)
• Nicotinamide-Nucleotide Adenylyltransferase
• Nucleic Acid Conformation
• Ovarian Neoplasms (metabolism, pathology)
• Poly(ADP-ribose) Polymerases (metabolism)
• Polyribosomes (metabolism)
• Protein Biosynthesis
• Proteostasis
• RNA, Messenger (chemistry, genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Ribosomal Proteins (metabolism)
• Ribosomes (metabolism)
• Mice