The ancient Z-DNA and Z-RNA specific Zα fold has evolved Modern Roles in Immunity and Transcription through the Natural Selection of Flipons

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The Zα fold specifically binds to both Z-DNA and Z-RNA, left-handed nucleic acid structures that form under physiological conditions and are encoded by flipons. I trace the Zα fold back to unicellular organisms representing all three domains of life and to the realm of giant nucleocytoplasmic viruses (NCV). The canonical Zα fold is present in the earliest known holozoan unicellular symbiont Capsaspora owczarzaki and persists in vertebrates and in some invertebrates, but not in plants or fungi. In metazoans, starting with porifera, Zα is incorporated into the double-stranded RNA editing enzyme ADAR and reflects an early symbiont relationship with NCV. In vertebrates, Zα is also present in ZBP1 and PKZ proteins that recognize host-derived Z-RNAs to defend against modern day viruses. A related Zα fold, also likely to bind Z-DNA, is present in proteins thought to modulate gene expression, including a subset of prokaryote arsR proteins and the p15 (PC4) family present in algae. Other Zα variants that likely play a more general role in the reinitiation of transcription include the archaeal and human transcription factor E (TFE) and the human RNA Polymerase 3 subunit C (POLR3C) proteins. The roles in immunity and transcription underlie the natural selection of flipons.