Suppression of ADP-ribosylation reversal triggers cell vulnerability to alkylating agents.

Autor:	Caggiano R; Institute of Experimental Endocrinology and Oncology, National Research Council of Italy, Naples, Italy., Prokhorova E; Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom., Duma L; Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom., Schützenhofer K; Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom., Lauro R; Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy., Catara G; Institute of Biochemistry and Cell Biology, National Research Council of Italy, Naples, Italy., Melillo RM; Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy., Celetti A; Institute of Experimental Endocrinology and Oncology, National Research Council of Italy, Naples, Italy., Smith R; Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom., Weroha SJ; Department of Oncology, Mayo Clinic, Rochester, Minnesota, United States., Kaufmann SH; Department of Oncology, Mayo Clinic, Rochester, Minnesota, United States., Ahel I; Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom. Electronic address: ivan.ahel@path.ox.ac.uk., Palazzo L; Institute of Experimental Endocrinology and Oncology, National Research Council of Italy, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy. Electronic address: luca.palazzo@unina.it.
Jazyk:	angličtina
Zdroj:	Neoplasia (New York, N.Y.) [Neoplasia] 2024 Nov 29; Vol. 59, pp. 101092. Date of Electronic Publication: 2024 Nov 29.
DOI:	10.1016/j.neo.2024.101092
Abstrakt:	The ADP-ribosyl hydrolases PARG and ARH3 counteract PARP enzymatic activity by removing ADP-ribosylation. PARG and ARH3 activities have a synthetic lethal effect; however, the specific molecular mechanisms underlying this response remain unknown. Here, we show that the PARG and ARH3 synthetic lethality is enhanced further in the presence of DNA alkylating agents, suggesting that the inability to revert ADP-ribosylation primarily affects the repair of alkylated DNA bases. ARH3 knockout cells, treated with PARG inhibitor and alkylating genotoxins, accumulated single-stranded DNA and DNA damage, resulting in G2/M cell cycle arrest and apoptosis. Furthermore, we reveal a reduction in PARP1/PARP2 levels in ARH3-deficient cells treated with PARG inhibitor due to excessive ADP-ribosylation, which may contribute to alkylating agents' vulnerability. Collectively, these results uncover the potential of targeting ADP-ribosyl hydrolases in combination with alkylating agents for cancer therapy and provide insights into the mechanisms underlying the synthetic lethal effect. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
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