Phosphorothioation: An Unusual Post-Replicative Modification on the DNA Backbone

DNA molecules are polymers composed of basic repeating subunits of deoxyribonucleotides, which consist of the deoxyribose sugar, phosphate groups, and a nitrogenous base. They appear to fulfill all requirements necessary to maintain the genetic function of DNA. The five elements of nitrogen, phosphorus, carbon, hydrogen, and oxygen had been regarded as the canonical composition of DNA until the discovery of phosphorothioation, with a sixth element, sulfur, identified as an additional naturally occurring constituent on the DNA backbone, as a sequence-selective, stereospecific postreplicative modification governed by the dnd gene cluster. Unlike any other DNA or RNA modification system, DNA phosphorothioation is the first-described physiological modification of the DNA sugar-phosphate backbone [1]. The physiological phosphorothioate modification is widespread in bacteria and occurs in diverse sequence contexts and frequencies in different bacterial genomes, implying a significant impact on bacteria [2]. Recently, a counterpart phosphorothioate-dependent restriction system capable of protection against the invasion of unmodified foreign DNA was discovered to maintain the genetic stability of the phosphorothioate modified host [3]. Another type IV endonuclease, ScoA3McrA, was found to be capable of specifically recognizing as well as cleaving phosphorothioate modified DNA [4]. Interestingly, the gene sco4631, which code for ScoA3McrA, is unable to coexist with the dnd gene cluster in the same host, causing immediate cell death [4]. Here we summarize the discovery of this first reported physiological modification on the DNA backbone, and provide insights and perspectives into the biological functions of the phosphorothioate modification in prokaryotic physiology.