| Summary: | Hydrogen sulfide (H<sub>2</sub>S) is a gasotransmitter that exerts numerous physiologic and pathophysiologic effects. Recently, a role for H<sub>2</sub>S in DNA repair has been identified, where H<sub>2</sub>S modulates cell cycle checkpoint responses, the DNA damage response (DDR), and mitochondrial and nuclear genomic stability. In addition, several DNA repair proteins modulate cellular H<sub>2</sub>S concentrations and cellular sulfur metabolism and, in turn, are regulated by cellular H<sub>2</sub>S concentrations. Many DDR proteins are now pharmacologically inhibited in targeted cancer therapies. As H<sub>2</sub>S and the enzymes that synthesize it are increased in many human malignancies, it is likely that H<sub>2</sub>S synthesis inhibition by these therapies is an underappreciated aspect of these cancer treatments. Moreover, both H<sub>2</sub>S and DDR protein activities in cancer and cardiovascular diseases are becoming increasingly apparent, implicating a DDR–H<sub>2</sub>S signaling axis in these pathophysiologic processes. Taken together, H<sub>2</sub>S 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 H<sub>2</sub>S in DNA repair.
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