Modular antibodies reveal DNA damage-induced mono-ADP-ribosylation as a second wave of PARP1 signaling
Year: 2023
Type: article
Abstract: PARP1, an established anti-cancer target that regulates many cellular pathways, including DNA repair signaling, has been intensely studied for decades as a poly(ADP-ribosyl)transferase. Although recent studies have revealed the prevalence of mono-ADP-ribosylation upon DNA damage, it was unknown whether this signal plays an active role in the cell or is just a byproduct of poly-ADP-ribosylation. By engineering SpyTag-based modular antibodies for sensitive and flexible detection of mono-ADP-ribosylation, including fluorescence-based sensors for live-cell imaging, we demonstrate that serine mono-ADP-ribosylation constitutes a second wave of PARP1 signaling shaped by the cellular HPF1/PARP1 ratio. Multilevel chromatin proteomics reveals histone mono-ADP-ribosylation readers, including RNF114, a ubiquitin ligase recruited to DNA lesions through a zinc-finger domain, modulating the DNA damage response and telomere maintenance. Our work provides a technological framework for illuminating ADP-ribosylation in a wide range of applications and biological contexts and establishes mono-ADP-ribosylation by HPF1/PARP1 as an important information carrier for cell signaling.
Source: Molecular Cell
Authors: Edoardo José Longarini, Helen Dauben, Carolina Locatelli, Anne R. Wondisford, Rebecca Smith, Charlotte Muench, Andreas Kolvenbach, Michelle Lee Lynskey, Alexis Pope, Juan José Bonfiglio, Eva Pinto Jurado, Roberta Fajka-Boja, Thomas Colby, Marion Schuller, Ivan Ahel, Gyula Timinszky, Roderick J. O’Sullivan, Sébastien Huet, Ivan Matic
Institutions: Max Planck Institute for Biology of Ageing, University of Pittsburgh, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Centre National de la Recherche Scientifique, Institut de génétique et de développement de Rennes, Structure Fédérative de Recherche en Biologie et Santé de Rennes, Université de Rennes, University of Szeged, HUN-REN Szegedi Biológiai Kutatóközpont, Institute of Genetics, Hungarian Research Network, University of Oxford, Institut Universitaire de France, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $9,080
Funders: Wellcome Trust, Ovarian Cancer Research Alliance, Cancer Research UK, European Commission, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Magyar Tudományos Akadémia, Fondation ARC pour la Recherche sur le Cancer, Institut Universitaire de France, Institut National Du Cancer, Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, Biotechnology and Biological Sciences Research Council, National Cancer Institute, National Institute of General Medical Sciences, H2020 European Research Council
Awards: G1662817063, G1888827638, G230613184, Serine ADP-ribosylation in genome stability and human disease, G2998518618, G3113876670, G3194705467, G3380221509, G381665449, G434337789, Serine ADP-ribosylation in genome stability and human disease, G5267018605, G5309921416, Protein poly(ADP-ribosyl)ation in genome stability and human disease., Decoding the DNA damage signalling in C. elegans by proteomic analyses of ADP-ribosylation, A multifaceted platform for exploring nucleotide-based post-translational modifications, G7240651115, G741073515, G8160935432, Understanding the activity and role of DarTG, a toxin:antitoxin system responsible for a novel DNA modification, Développment d'une infrastructure française distribuée coordonnée, G8723269792, Inhibition of the ALT pathway by interfering with Poly-ADP-Ribose metabolism, Predoctoral Training in Pharmacological Sciences
OpenAlex ID: W4367322410