Selenium (Se) is an essential element to humans and animals. Since its diverse functions were discovered, its importance has been more and more revealed. After the discovery of selenium as a key component of many proteins, significant research efforts have been focused on its therapeutic and nutritional potentials and possible impacts on human and animal health. To date, 25 selenoprotein genes have been identified in humans and animals, where selenium exists in the form of an amino acid, selenocysteine (Sec). Sec incorporation into selenoproteins occurs through a unique process by recognizing UGA stop codon via the Sec-charged tRNA for delivering Sec into proteins. Most selenoproteins are antioxidant proteins and play critical roles in maintaining redox balance in living systems by removing reactive oxygen species (ROS) and/or reactive nitrogen species (RNS). These reactive species are major threats to bio-macromolecules, such as DNAs, RNAs, proteins, lipids, and carbohydrates. They may cause molecular oxidation and DNA damage/mutation, alter gene expression patterns, weaken the immune system, and even lead to neurological disorders and other pathological conditions. As potential drugs and/or nutritional supplements, selenium-functionalized molecules (SeFMs) have shown benefits in preventing and/or treating many diseases, such as cancer, cardiovascular diseases, thyroid diseases, diabetes, AIDS, rheumatoid arthritis (RA), and neurodegenerative diseases. These promising results and therapeutic potentials of SeFMs have attracted tremendous attention from academia and pharmaceutical and biotech industries. However, further fundamental research and investigation are required to discover the ideal chemical, biochemical, and biological forms of selenium, appropriate dosages, and mechanisms of the selenium biological

The crystal structures of protein-nucleic acid complexes are commonly determined using selenium-derivatized proteins via MAD or SAD phasing. Here, the first protein-nucleic acid complex structure determined using selenium-derivatized nucleic acids is reported. The RNase H-RNA/DNA complex is used as an example to demonstrate the proof of principle. The high-resolution crystal structure indicates that this selenium replacement results in a local subtle unwinding of the RNA/DNA substrate duplex, thereby shifting the RNA scissile phosphate closer to the transition state of the enzyme-catalyzed reaction. It was also observed that the scissile phosphate forms a hydrogen bond to the water nucleophile and helps to position the water molecule in the structure. Consistently, it was discovered that the substitution of a single O atom by a Se atom in a guide DNA sequence can largely accelerate RNase H catalysis. These structural and catalytic studies shed new light on the guide-dependent RNA cleavage.

RNA can catalyze and participate in many chemical and biochemical reactions. Non-coding RNAs (ncRNA) can regulate cellular transcription and translation reactions. We have demonstrated biochemically that RNA can also interfere with DNA polymerization via transforming DNA polymerase into deoxyribonucleoside triphosphate diphosphatase (dNTP-DPase). RNA, even with six nucleotides, can transform DNA polymerase into dNTP-DPase, and the dNTP-DPase activity causes the hydrolysis of dNTPs into dNMPs and pyrophosphate. Moreover, we have found that DNA polymerases from several families generally have similar RNA-dependent dNTP-DPase activity. We have also observed that in the presence of RNA, when the dNTP concentrations are relatively low, and that the dNTP-DPase activity can deplete dNTPs and interfere with DNA polymerization. Thus, we have discovered for the first time that in the presence of RNA, DNA polymerase can behave as a diphosphatase and inhibit DNA synthesis when dNTP quantity is low. These in vitro observations might imply a plausible role of RNA in vivo, such as suppressing DNA synthesis during a resting phase (G0) of the cell cycle, when RNA quantity is high and dNTP quantity is low.

Nucleic acids and their modifications are instrumental in discovering functional oligonucleotides as important biochemical and therapeutic agents. In the search of bioactive compounds, a variety of synthetic strategies have been developed to design novel analogs of the nucleosides, nucleotides, and nucleic acids. Since oxygen atoms are found in abundance in natural nucleic acids, the atom-specific replacement of these oxygen atoms with the heavier chalcogens sulfur, selenium, and tellurium facilitates generation of novel nucleic acids with distinctive properties, such as enhanced duplex stability, binding affinity, nuclease resistance, bioavailability, and base-pair fidelity. These structural alterations create a new archetype of nucleic acids with potential applications in therapeutics and drug development. Moreover, these engineered nucleic acids are useful biological tools for disease detection, molecular sensing, and fundamental understanding of nucleic acid structures and functions. This review outlines sulfur, selenium, and tellurium modifications to nucleic acids and their role in generating new classes of nucleic acids with tunable biochemical and physico-chemical properties. Such modifications offer structural, functional, and mechanistic probes for investigating the structures and biological functions of nucleic acids (DNA and RNA).

6-Se-guanosine phosphoramidite and RNAs have been synthesized by selenium substitution of the 6-oxygen atom, and it is revealed that the Se-derivatization is relatively stable and that bulge and wobble structures can better accommodate a large Se atom than a duplex. This Se-modification is useful in the structural study of RNAs and their protein complexes.