@article{8ea06a7316344a68948ab594d9f16e33,
title = "Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21",
abstract = "PARP inhibitors (PARPi) prevent cancer cell growth by inducing synthetic lethality with DNA repair defects (e.g., in BRCA1/2 mutant cells). We have identified an alternative pathway for PARPi-mediated growth control in BRCA1/2-intact breast cancer cells involving rDNA transcription and ribosome biogenesis. PARP-1 binds to snoRNAs, which stimulate PARP-1 catalytic activity in the nucleolus independent of DNA damage. Activated PARP-1 ADP-ribosylates DDX21, an RNA helicase that localizes to nucleoli and promotes rDNA transcription when ADP-ribosylated. Treatment with PARPi or mutation of the ADP-ribosylation sites reduces DDX21 nucleolar localization, rDNA transcription, ribosome biogenesis, protein translation, and cell growth. The salient features of this pathway are evident in xenografts in mice and human breast cancer patient samples. Elevated levels of PARP-1 and nucleolar DDX21 are associated with cancer-related outcomes. Our studies provide a mechanistic rationale for efficacy of PARPi in cancer cells lacking defects in DNA repair whose growth is inhibited by PARPi.",
keywords = "ADP-ribosylation, DDX21, PARP inhibitor, PARP-1, breast cancer, poly(ADP-ribose) polymerase-1, rDNA transcription, ribosome biogenesis, small nucleolar RNAs, snoRNAs",
author = "Kim, {Dae Seok} and Camacho, {Cristel V.} and Anusha Nagari and Malladi, {Venkat S.} and Sridevi Challa and Kraus, {W. Lee}",
note = "Funding Information: We thank the following for their assistance: Minho Chae for assistance with analysis of sequencing data, Keun Woo Ryu for the recombinant PARP-1 deletion mutants, Tim Hou for the polyA-enriched and polyA-depleted RNA-seq data, Rebecca Gupte for the FACS analysis, Yang Peng for assistance with pathology analyses, and Shrikanth Gadad and Bryan Gibson for intellectual input and critical comments on this manuscript. We also acknowledge and thank the following UT Southwestern core facilities: the Live Cell Imaging Core for microscopy support (Dr. Katherine Luby-Phelps), the Next Generation Sequencing Core for deep sequencing services (Vanessa Schmid), the Histo Pathology Core for histology services, and the Tissue Management Shared Resource for providing human tissues and immunohistochemical support. This work was supported by a postdoctoral fellowship from the U.S. Department of Defense (DOD) Breast Cancer Research Program (BC134066) to D.-S.K. This work was also supported by a grant from the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK058110) and funds from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment to W.L.K. D.-S.K. and W.L.K. conceived this project, designed the experiments, and oversaw their execution. D.-S.K. performed all of the biochemical and cell-based experiments. C.V.C. and D.-S.K. performed the in vivo mouse experiments and the experiments with human cancer samples, and S.C. and D.-S.K. performed the ribosome fractionation assay. A.N. and V.S.M. analyzed the RIP-seq and RNA-seq data. D.-S.K. prepared the initial drafts of the figures and text, which were edited by C.V.C. and W.L.K. 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. He is also co-holder 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 the following for their assistance: Minho Chae for assistance with analysis of sequencing data, Keun Woo Ryu for the recombinant PARP-1 deletion mutants, Tim Hou for the polyA-enriched and polyA-depleted RNA-seq data, Rebecca Gupte for the FACS analysis, Yang Peng for assistance with pathology analyses, and Shrikanth Gadad and Bryan Gibson for intellectual input and critical comments on this manuscript. We also acknowledge and thank the following UT Southwestern core facilities: the Live Cell Imaging Core for microscopy support (Dr. Katherine Luby-Phelps), the Next Generation Sequencing Core for deep sequencing services (Vanessa Schmid), the Histo Pathology Core for histology services, and the Tissue Management Shared Resource for providing human tissues and immunohistochemical support. This work was supported by a postdoctoral fellowship from the U.S. Department of Defense (DOD) Breast Cancer Research Program ( BC134066 ) to D.-S.K. This work was also supported by a grant from the NIH / National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( R01 DK058110 ) and funds from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment to W.L.K. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = sep,
day = "19",
doi = "10.1016/j.molcel.2019.06.020",
language = "English (US)",
volume = "75",
pages = "1270--1285.e14",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}