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

Hydrogen sulfide (H(2)S) is a gasotransmitter that exerts numerous physiologic and pathophysiologic effects. Recently, a role for H(2)S in DNA repair has been identified, where H(2)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(2)S concentrations and cellular sulfur metabolism and, in turn, are regulated by cellular H(2)S concentrations. Many DDR proteins are now pharmacologically inhibited in targeted cancer therapies. As H(2)S and the enzymes that synthesize it are increased in many human malignancies, it is likely that H(2)S synthesis inhibition by these therapies is an underappreciated aspect of these cancer treatments. Moreover, both H(2)S and DDR protein activities in cancer and cardiovascular diseases are becoming increasingly apparent, implicating a DDR–H(2)S signaling axis in these pathophysiologic processes. Taken together, H(2)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(2)S in DNA repair.