Structure and Formation of Z-DNA and Z-RNA

Abstract

Despite structural differences between the right-handed conformations of A-RNA and B-DNA, both nucleic acids adopt very similar, left-handed Z-conformations. In contrast to their structural similarities and sequence preferences, RNA and DNA exhibit differences in their ability to adopt the Z-conformation regarding their hydration shells, the chemical modifications that promote the Z-conformation, and the structure of junctions connecting them to right-handed segments. In this review, we highlight the structural and chemical properties of both Z-DNA and Z-RNA and delve into the potential factors that contribute to both their similarities and differences. While Z-DNA has been extensively studied, there is a gap of knowledge when it comes to Z-RNA. Where such information is lacking, we try and extend the principles of Z-DNA stability and formation to Z-RNA, considering the inherent differences of the nucleic acids.

Z-Form Adoption of Nucleic Acid is a Multi-Step Process Which Proceeds through a Melted Intermediate

“…This would allow for the Z-conformation to be adopted more easily and thus promote Zα binding. These sequence elements are quite common in long dsRNA formed from repetitive elements, − such as Alu elements in humans and viral RNAs. − However, too many destabilizing base pairs would eventually cause the adopted Z-conformation to also become destabilized . This would also be impacted by the number of pyrimidine-purine repeats, which determine the final stability of the adopted Z-conformation .…”

“…These sequence elements are quite common in long dsRNA formed from repetitive elements, − such as Alu elements in humans and viral RNAs. − However, too many destabilizing base pairs would eventually cause the adopted Z-conformation to also become destabilized . This would also be impacted by the number of pyrimidine-purine repeats, which determine the final stability of the adopted Z-conformation . Therefore, there is likely a balance between the ease of helix melting and the stability of the adopted Z-conformation, which determines the adoption rate and overall longevity of Z-conformations in the cell.…”

“…9 This would also be impacted by the number of pyrimidine-purine repeats, which determine the final stability of the adopted Z-conformation. 9 Therefore, there is likely a balance between the ease of helix melting and the stability of the adopted Z-conformation, which determines the adoption rate and overall longevity of Z-conformations in the cell. In addition to the RNA sequence itself, many potential trans-acting factors would also be predicted to promote Z-form adoption, including helicase activity 110 and torsional/mechanical stress, 93 which would facilitate duplex melting and, therefore, promote Z-form adoption as previously hypothesized.…”

“…Nucleic acid binding proteins often exploit this fact in order to selectively recognize DNA or RNA. , Interestingly, both DNA and RNA will adopt a higher-energy, left-handed double-stranded conformation known as the Z-form under certain conditions (Figure A), such as when recognized and stabilized by Z-DNA/Z-RNA-binding Zα domains − or through chemical conditions/modifications (extensively reviewed here). Other than the inverted helicity, the Z-conformation is more elongated compared to B-DNA/A-RNA and is composed of a repeating dinucleotide unit where the sugar puckers alternate between the C2′- and C3′-endo conformation along with the bases between the anti- and syn-conformations. ,− This arrangement leads to a lone pair−π contact only found within Z geometry (involving the O4′ of the C2′-endo sugar and the syn base , ). The unique features of Z-form helices result in a jagged backbone conformation which “zig-zags” along the helical axis.…”

Chemistry, structure and function of approved oligonucleotide therapeutics

“…Base pairs in B-DNA are more or less normal to the direction of the helical axis, with an average rise of 3.4 Å and 10 base pairs per turn. DNA can also adopt the A-form ( 104 ) and flip to left-handed Z-DNA ( 105 , 106 ) as a result of torsional stress and dependent on sequence (CG-rich), ionic strength ( 107 ) and hydration level ( 108 ).…”