. 2020 Feb; 34(5-6):302-320.
doi: 10.1101/gad.334433.119.

PARPs and ADP-ribosylation in RNA biology: from RNA expression and processing to protein translation and proteostasis

Dae-Seok Kim 1 Sridevi Challa 1 Aarin Jones 1 W Lee Kraus 1 
  • PMID: 32029452
  •     156 References
  •     17 citations


ADP-ribosylation (ADPRylation) is a posttranslational modification of proteins discovered nearly six decades ago, but many important questions remain regarding its molecular functions and biological roles, as well as the activity of the ADP-ribose (ADPR) transferase enzymes (PARP family members) that catalyze it. Growing evidence indicates that PARP-mediated ADPRylation events are key regulators of the protein biosynthetic pathway, leading from rDNA transcription and ribosome biogenesis to mRNA synthesis, processing, and translation. In this review we describe the role of PARP proteins and ADPRylation in all facets of this pathway. PARP-1 and its enzymatic activity are key regulators of rDNA transcription, which is a critical step in ribosome biogenesis. An emerging role of PARPs in alternative splicing of mRNAs, as well as direct ADPRylation of mRNAs, highlight the role of PARP members in RNA processing. Furthermore, PARP activity, stimulated by cellular stresses, such as viral infections and ER stress, leads to the regulation of mRNA stability and protein synthesis through posttranscriptional mechanisms. Dysregulation of PARP activity in these processes can promote disease states. Collectively, these results highlight the importance of PARP family members and ADPRylation in gene regulation, mRNA processing, and protein abundance. Future studies in these areas will yield new insights into the fundamental mechanisms and a broader utility for PARP-targeted therapeutic agents.

Keywords: ADP-ribosylation (ADPRylation); DNA damage; PARP inhibitors (PARPi); RNA stability; mRNA processing; mRNA splicing; mRNA translation; mono(ADP-ribose) (MAR); poly(ADP-ribose) (PAR); poly(ADP-ribose) polymerase (PARP); rRNA synthesis; ribosome biogenesis; stress responses.

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Nat Methods, 2013 Aug 21; 10(10). PMID: 23955771
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The NMN/NaMN adenylyltransferase (NMNAT) protein family.
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Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation.
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Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation.
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Nat Commun, 2017 Dec 22; 8(1). PMID: 29263426    Free PMC article.
PARP-1 and PARP-2 interact with nucleophosmin/B23 and accumulate in transcriptionally active nucleoli.
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J Cell Sci, 2004 Dec 24; 118(Pt 1). PMID: 15615785
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Increased poly(ADP-ribosyl)ation of nuclear proteins in Alzheimer's disease.
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A Cell-Line-Specific Atlas of PARP-Mediated Protein Asp/Glu-ADP-Ribosylation in Breast Cancer.
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Cell Rep, 2017 Nov 23; 21(8). PMID: 29166620    Free PMC article.
Protein Misfolding and ER Stress in Huntington's Disease.
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Sorting out the complexity of SR protein functions.
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Coupling of PARP1-mediated chromatin structural changes to transcriptional RNA polymerase II elongation and cotranscriptional splicing.
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TCDD-inducible poly-ADP-ribose polymerase (TIPARP/PARP7) mono-ADP-ribosylates and co-activates liver X receptors.
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Cell, 2012 Jun 05; 149(6). PMID: 22658674
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The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson's Disease.
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Yingqun Huang, Joan A Steitz.
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Quantitative proteomics profiling of the poly(ADP-ribose)-related response to genotoxic stress.
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Mol Cell, 2012 Mar 13; 45(6). PMID: 22405650
PARP16/ARTD15 is a novel endoplasmic-reticulum-associated mono-ADP-ribosyltransferase that interacts with, and modifies karyopherin-ß1.
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PARP1 represses PAP and inhibits polyadenylation during heat shock.
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CpG Dinucleotides Inhibit HIV-1 Replication through Zinc Finger Antiviral Protein (ZAP)-Dependent and -Independent Mechanisms.
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Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization.
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PARPs and ADP-ribosylation: 60 years on.
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Revealing the selective mechanisms of inhibitors to PARP-1 and PARP-2 via multiple computational methods.
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The Nucleolus and PARP1 in Cancer Biology.
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Specific Binding of snoRNAs to PARP-1 Promotes NAD+-Dependent Catalytic Activation.
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ADPriboDB v2.0: An Updated Database of ADP-ribosylated Proteins.
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KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma.
Xiuzhi Zhang, Jialing Zhang, +3 authors, Jinzhong Zhang.
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Cells, 2021 Jan 15; 10(1). PMID: 33440786    Free PMC article.
Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance.
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Identification of PARP-7 substrates reveals a role for MARylation in microtubule control in ovarian cancer cells.
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The SARS-CoV-2 Conserved Macrodomain Is a Mono-ADP-Ribosylhydrolase.
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ADP-ribosylation of RNA and DNA: from in vitro characterization to in vivo function.
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Repositioning PARP inhibitors for SARS-CoV-2 infection(COVID-19); a new multi-pronged therapy for acute respiratory distress syndrome?
Nicola Curtin, Krisztián Bányai, +3 authors, Péter Bai.
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