Modular antibodies reveal DNA damage-induced mono-ADP-ribosylation as a second wave of PARP1 signaling

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 whet...

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Detalles Bibliográficos
Autores principales: Longarini, Edoardo José, Dauben, Helen, Locatelli, Carolina, Wondisford, Anne R., Smith, Rebecca, Muench, Charlotte, Kolvenbach, Andreas, Lynskey, Michelle Lee, Pope, Alexis, Bonfiglio, Juan José, Jurado, Eva Pinto, Fajka-Boja, Roberta, Colby, Thomas, Schuller, Marion, Ahel, Ivan, Timinszky, Gyula, O’Sullivan, Roderick J., Huet, Sébastien, Matic, Ivan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2023
Materias:
Technology
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10205078/
https://www.ncbi.nlm.nih.gov/pubmed/37116497
http://dx.doi.org/10.1016/j.molcel.2023.03.027
Descripción
Sumario: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.

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