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Proc Natl Acad Sci U S A. 2019 Oct 22;116(43):21521-21528. doi: 10.1073/pnas.1909283116. Epub 2019 Oct 4.

Caspase-7 uses RNA to enhance proteolysis of poly(ADP-ribose) polymerase 1 and other RNA-binding proteins.

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Institut de pharmacolgie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
Centre de recherche du CHUS, Sherbrooke, QC J1H 5N4, Canada.
Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
Institut de pharmacolgie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada;


To achieve swift cell demise during apoptosis, caspases cleave essential proteins for cell survival and removal. In addition to the binding of preferred amino acid sequences to its substrate-binding pocket, caspase-7 also uses exosites to select specific substrates. 4 lysine residues (K38KKK) located in the N-terminal domain of caspase-7 form such an exosite and promote the rapid proteolysis of the poly(ADP-ribose) polymerase 1 (PARP-1), but the mechanism of recognition remains mostly unknown. In this study, we show that the overall positive charge of the exosite is the critical feature of this evolutionarily conserved binding site. Additionally, interaction with the caspase-7 exosite involves both the Zn3 and BRCT domains of PARP-1 and is mediated by RNA. Indeed, PARP-1 proteolysis efficacy is sensitive to RNase A and promoted by added RNA. Moreover, using affinity chromatography and gel shift assays, we demonstrate that caspase-7, but not caspase-3 or a caspase-7 with a mutated exosite, binds nucleic acids. Finally, we show that caspase-7 prefers RNA-binding proteins (RNA-BPs) as substrates compared to caspase-3 and that RNA enhances proteolysis by caspase-7 of many of these RNA-BPs. Thus, we have uncovered an unusual way by which caspase-7 selects and cleaves specific substrates.


RNA-BPs; apoptosis; caspase-7; exosite; poly(ADP-ribose) polymerase 1

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