Z-DNA and Z-RNA: Methods—Past and Future

Herbert, Alan

doi:10.1007/978-1-0716-3084-6_21

Cited by 3 publications

(6 citation statements)

References 153 publications

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“…Such results are illustrative yet inconclusive, inasmuch as the full extent of the protein–protein and protein–nucleic acid interactions of the homodimer is not represented. Fortunately, a control parallel exercise with the Zα domain ( Table 3 ) reproduced the majority of residues and contacts denoted as idiosyncratic of the Zα family, based on extensive biophysical characterization [ 14 , 15 , 16 , 17 , 18 , 19 ]. The differences in the orientations of the two Z-domains relative to the DNAs are remarkable and await elucidation by high-resolution structure determinations.…”

Section: Resultsmentioning

confidence: 99%

“…For example, two tryptophan residues (W860 and W931) are involved in the crystal structure with bent B-DNA (4fm9). Tryptophan is a critical and well-described Z-DNA-binding residue in the Zα domain [ 18 , 20 , 23 ], and in 4fm9, W860 is in direct contact with the DNA backbone. In addition, it is at the center of the putative GTP-binding region predicted in this report.…”

Section: Resultsmentioning

confidence: 99%

“…One of them is the potential equilibration between local B- and Z-conformations in the absence of topoII, i.e., depending on factors such as DNA sequence, state of deformation from torsion (supercoiling), tension (stretching), bending, and solution parameters (temperature, salt composition, small effector molecules such as polyamines, ionic strength, dielectric constant). Such sequence domains that can fluctuate relatively easily between the left- and right-handed helical conformations constitute the class of Z-flipons introduced by Allan Herbert for DNA (and RNA) sequences that “flip” into the Z-conformation, are recognized by ZBPs [ 79 ] and thereby exert a number of cell biological functions [ 17 , 18 , 20 ]. For sequences that require the putative conformase function of topoII to adopt and stabilize a left-handed conformation ( fp3 , Table 4 ), we propose the new term Z-flipins .…”

Section: Resultsmentioning

confidence: 99%

“…The second is the family of “non-B” DNA structures [ 5 ] deemed to intervene in cellular processes [ 6 ], one of which is the “Z-DNA” double helix with a left-handed helical sense, first proposed in 1970–1972 based on solution studies of alternating pur-pyr d[G-C] sequences [ 7 , 8 ] and confirmed by X-ray crystallography a decade later [ 9 , 10 ]. The structures and generation of Z-DNA and related Z-RNA have been reviewed recently [ 11 , 12 , 13 ], as have the biological roles attributed to them [ 14 , 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Extensive Bioinformatics Analyses Reveal a Phylogenetically Conserved Winged Helix (WH) Domain (Zτ) of Topoisomerase IIα, Elucidating Its Very High Affinity for Left-Handed Z-DNA and Suggesting Novel Putative Functions

Bartas

Slychko

Červeň

et al. 2023

IJMS

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The dynamic processes operating on genomic DNA, such as gene expression and cellular division, lead inexorably to topological challenges in the form of entanglements, catenanes, knots, “bubbles”, R-loops, and other outcomes of supercoiling and helical disruption. The resolution of toxic topological stress is the function attributed to DNA topoisomerases. A prominent example is the negative supercoiling (nsc) trailing processive enzymes such as DNA and RNA polymerases. The multiple equilibrium states that nscDNA can adopt by redistribution of helical twist and writhe include the left-handed double-helical conformation known as Z-DNA. Thirty years ago, one of our labs isolated a protein from Drosophila cells and embryos with a 100-fold greater affinity for Z-DNA than for B-DNA, and identified it as topoisomerase II (gene Top2, orthologous to the human UniProt proteins TOP2A and TOP2B). GTP increased the affinity and selectivity for Z-DNA even further and also led to inhibition of the isomerase enzymatic activity. An allosteric mechanism was proposed, in which topoII acts as a Z-DNA-binding protein (ZBP) to stabilize given states of topological (sub)domains and associated multiprotein complexes. We have now explored this possibility by comprehensive bioinformatic analyses of the available protein sequences of topoII representing organisms covering the whole tree of life. Multiple alignment of these sequences revealed an extremely high level of evolutionary conservation, including a winged-helix protein segment, here denoted as Zτ, constituting the putative structural homolog of Zα, the canonical Z-DNA/Z-RNA binding domain previously identified in the interferon-inducible RNA Adenosine-to-Inosine-editing deaminase, ADAR1p150. In contrast to Zα, which is separate from the protein segment responsible for catalysis, Zτ encompasses the active site tyrosine of topoII; a GTP-binding site and a GxxG sequence motif are in close proximity. Quantitative Zτ-Zα similarity comparisons and molecular docking with interaction scoring further supported the “B-Z-topoII hypothesis” and has led to an expanded mechanism for topoII function incorporating the recognition of Z-DNA segments (“Z-flipons”) as an inherent and essential element. We further propose that the two Zτ domains of the topoII homodimer exhibit a single-turnover “conformase” activity on given G(ate) B-DNA segments (“Z-flipins”), inducing their transition to the left-handed Z-conformation. Inasmuch as the topoII-Z-DNA complexes are isomerase inactive, we infer that they fulfill important structural roles in key processes such as mitosis. Topoisomerases are preeminent targets of anti-cancer drug discovery, and we anticipate that detailed elucidation of their structural–functional interactions with Z-DNA and GTP will facilitate the design of novel, more potent and selective anti-cancer chemotherapeutic agents.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Extensive Bioinformatics Analyses Reveal a Phylogenetically Conserved Winged Helix (WH) Domain (Zτ) of Topoisomerase IIα, Elucidating Its Very High Affinity for Left-Handed Z-DNA and Suggesting Novel Putative Functions

Bartas

Slychko

Červeň

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…These UNas are also believed to play crucial roles in innate immunity and host-virus interactions [19]. Proteins preferentially recognizing left-handed nucleic acids are known [20][21][22][23].…”

Section: Overview Of Unusual Nucleic Acid Structuresmentioning

confidence: 99%