@article{439d8da156e54bbc8cd568fed018630b,
title = "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.",
keywords = "ADP-ribosylation, MARylation, NAD, NAD sensor, NAD synthesis, NMNAT-2, PARP-16, cancer, mRNA translation, mono(ADP-ribose), mono(ADP-ribosyl)ation, ovarian cancer, protein aggregation, protein synthesis, ribosomes, translation",
author = "Sridevi Challa and Khulpateea, {Beman R.} and Tulip Nandu and Camacho, {Cristel V.} and Ryu, {Keun W.} and Hao Chen and Yan Peng and Lea, {Jayanthi S.} and Kraus, {W. Lee}",
note = "Funding Information: We thank Dr. Andrew Kelleher and Dr. Rebecca Gupte for critical comments on this manuscript. We also thank Dr. Xiaolu Cambronne and Dr. Michael Cohen for the cpVenus-based NAD+ sensors and PARP-16 constructs. We acknowledge and thank the following UT Southwestern core facilities: Live Cell Imaging Core for microscopy support (Dr. Katherine Luby-Phelps), Next Generation Sequencing Core for deep sequencing services (Vanessa Schmid), Proteomics Core Facility for identification of sites of MARylation (Dr. Andrew Lemoff), Histopathology Core for histology services, Tissue Management Shared Resource for providing human tissues and immunohistochemical support, and the Whole Brain Microscopy Facility for imaging TMA slides (Dr. Denise Ramirez). This work was supported by NIH/NIDDK (R01 DK069710 to W.L.K.), the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment (to W.L.K.), and a postdoctoral fellowship from the Ovarian Cancer Research Alliance (GAA202103-0003 to S.C.). S.C. and W.L.K. conceived this project, designed the experiments, and oversaw their execution. S.C. performed all of the biochemical and cell-based experiments. C.V.C. and S.C. performed the experiments with mouse xenograft and human cancer samples. T.N. analyzed the polysome RNA-seq data. K.W.R. assisted with imaging the NAD+ sensor experiments. B.R.K. Y.P. and J.S.L. obtained IRB approval and oversaw patient sample collection. B.R.K. gathered the clinical data. H.C. scored the IHC staining. S.C. prepared the initial drafts of the figures and text, which were edited and finalized by W.L.K. W.L.K secured funding to support this project and provided intellectual support for all aspects of the work. W.L.K. is a founder and consultant for Ribon Therapeutics, Inc. and ARase Therapeutics, Inc. He is also coholder of U.S. Patent 9,599,606 covering the ADP-ribose detection reagent used herein, which has been licensed to and is sold by EMD Millipore. Funding Information: We thank Dr. Andrew Kelleher and Dr. Rebecca Gupte for critical comments on this manuscript. We also thank Dr. Xiaolu Cambronne and Dr. Michael Cohen for the cpVenus-based NAD + sensors and PARP-16 constructs. We acknowledge and thank the following UT Southwestern core facilities: Live Cell Imaging Core for microscopy support (Dr. Katherine Luby-Phelps), Next Generation Sequencing Core for deep sequencing services (Vanessa Schmid), Proteomics Core Facility for identification of sites of MARylation (Dr. Andrew Lemoff), Histopathology Core for histology services, Tissue Management Shared Resource for providing human tissues and immunohistochemical support, and the Whole Brain Microscopy Facility for imaging TMA slides (Dr. Denise Ramirez). This work was supported by NIH/NIDDK ( R01 DK069710 to W.L.K.), the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment (to W.L.K.), and a postdoctoral fellowship from the Ovarian Cancer Research Alliance ( GAA202103-0003 to S.C.). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = aug,
day = "19",
doi = "10.1016/j.cell.2021.07.005",
language = "English (US)",
volume = "184",
pages = "4531--4546.e26",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "17",
}