Intracellular H2S production is an autophagy-dependent adaptive response to DNA damage. Issue 12 (16th December 2021)

• Record Type: Journal Article
• Authors: Jiang, Xiaofeng; MacArthur, Michael R.; Treviño-Villarreal, J. Humberto; Kip, Peter; Ozaki, C. Keith; Mitchell, Sarah J.; Mitchell, James R.
• Is Part Of: Cell chemical biology. Volume 28:Issue 12(2021)
• Page Start: 1669
• Page End: 1678.e5
• Publication Date: 2021-12-16
• Subjects: hydrogen sulfide -- sulfide metabolism -- autophagy -- CGL enzyme -- DNA damage response -- cancer chemotherapy -- stress response -- high-throughput screening -- P3 probe -- SF7-AM probe; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2021.05.016
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Hydrogen sulfide (H2 S) is a gasotransmitter with broad physiological activities, including protecting cells against stress, but little is known about the regulation of cellular H2 S homeostasis. We have performed a high-content small-molecule screen and identified genotoxic agents, including cancer chemotherapy drugs, as activators of intracellular H2 S levels. DNA damage-induced H2 S in vitro and in vivo . Mechanistically, DNA damage elevated autophagy and upregulated H2 S-generating enzyme CGL; chemical or genetic disruption of autophagy or CGL impaired H2 S induction. Importantly, exogenous H2 S partially rescued autophagy-deficient cells from genotoxic stress. Furthermore, stressors that are not primarily genotoxic (growth factor depletion and mitochondrial uncoupler FCCP) increased intracellular H2 S in an autophagy-dependent manner. Our findings highlight the role of autophagy in H2 S production and suggest that H2 S generation may be a common adaptive response to DNA damage and other stressors. Graphical abstract: Highlights: A high-content screen identifies genotoxic agents as activators of cellular H2 S levels DNA damage increases intracellular H2 S, sulfane sulfide, and extracellular H2 S levels Autophagy and CGL enzyme regulate H2 S induction upon DNA damage Autophagy-dependent H2 S induction may be a general adaptive response to stress Abstract : Jiang et al. developed a high-content screen and identified genotoxic agents as activators of intracellular H2 S levels. H2 S induction is a physiological DNA damage response and is regulated by autophagy and CGL enzyme. Autophagy-dependent H2 S induction may be a general adaptive response to stress.