Abstract
Hydrogen sulfide (H2S) is a gasotransmitter that exerts numerous physiologic and pathophysiologic effects. Recently, a role for H2S in DNA repair has been identified, where H2S modulates cell cycle checkpoint responses, the DNA damage response (DDR), and mitochondrial and nuclear genomic stability. In addition, several DNA repair proteins modulate cellular H2S concentrations and cellular sulfur metabolism and, in turn, are regulated by cellular H2S concentrations. Many DDR proteins are now pharmacologically inhibited in targeted cancer therapies. As H2S and the enzymes that synthesize it are increased in many human malignancies, it is likely that H2S synthesis inhibition by these therapies is an underappreciated aspect of these cancer treatments. Moreover, both H2S and DDR protein activities in cancer and cardiovascular diseases are becoming increasingly apparent, implicating a DDR–H2S signaling axis in these pathophysiologic processes. Taken together, H2S and DNA repair likely play a central and presently poorly understood role in both normal cellular function and a wide array of human pathophysiologic processes. Here, we review the role of H2S in DNA repair.
Highlights
The maintenance of genomic stability is essential for life, and cells have evolved complex and intricate molecular machinery to ensure DNA stability and accurate DNA replication [1,2,3,4]
This study indicates that cystathionine γ-lyase (CSE)-generated Hydrogen sulfide (H2 S) acts as a DNA damage protectant, S-sulfhydrating MEK1 Cys 341, activating ERK1/2 and PARP-1 to repair DNA damage [13]
Treatment of wild-type and ATG5 knockout murine embryonic fibroblasts (MEFs) with PAG decreased teniposide-induced H2 S in both cell types. These results suggest an additive role for ATF4-mediated CSE expression and autophagy in H2 S
Summary
The maintenance of genomic stability is essential for life, and cells have evolved complex and intricate molecular machinery to ensure DNA stability and accurate DNA replication [1,2,3,4]. The mitochondrial genome is circular, contains 37 genes in 16,569 base pairs, and occurs in multiple copies at 100–1000/cell [4,5]. DNA repair, while mitochondrial genomic damage can initiate apoptotic cell death via cytochrome c release and can activate the innate immune response [4,5,6,7]. H2 S has been found to regulate mitochondrial and nuclear DNA stability and repair [11,12,13]. We review this new area of inquiry and discuss its possible implications for cancer chemotherapy and cardiovascular diseases.
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