Bad Smells and Broken DNA: A Tale of Sulfur-Nucleic Acid Cooperation

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.