ABSTRACT
I return to work with Alex Rich, whose story I describe, on the Z-DNA problem. The quest was to find any protein that recognized this conformation and then to work out a biological role if such a protein existed. The approaches we initially used failed completely and we and others were unable to validate the existence of any protein that bound specifically to Z-DNA. After three years, there was not much to show for a lot of effort. I had, however, developed a new method robust enough to detect a Z-DNA binding protein, if there was one to be found. However, I still didn’t know whether a Z-DNA binding protein existed in a cell, and I didn’t know whether it would only bind to a particular sequence of Z-DNA. I also didn’t know which tissue or cell to look in to find if such a protein was there. In 1993, I published the first evidence for the existence of a Z-DNA binding protein with a domain I called Zα, hoping it would be the first of many. In 1995, we purified the protein with the Zα domain and identified it as the RNA-editing protein ADAR1. In 1997, I identified the residues encoding Zα and other members of the family called E3 and ZBP1. In 1999, we published the structure of Zα which bound to Z-DNA. In 2001, I showed that a mutation to a residue in Zα reduced the editing of short substrates in cells.
This chapter describes what happened next. We discovered that the protein called ADAR1, that had the Zα domain, performed RNA editing of transcripts from a gene. It changed a specific RNA base in a messenger RNA and recoded an amino acid in the protein product. While this was an exciting discovery, the biological relevance of editing at the time was unknown. The last thing people in this field wanted was to be tarred by anything to do with Z-DNA. Indeed, the Z-DNA domain I discovered in this protein was rarely mentioned in the talks by the RNA editing people – it was as if the domain did not exist. The editing field entered its own down-cycle when it was shown in mice that recoding of protein by editing had only one role in development – that is, in correcting a mutation in a nerve cell ion channel. However, the discoveries have yielded a new form of gene therapy that does not involve changing the DNA sequence as with gene editing approaches based on CRISPR. Instead, you correct genetic disease by editing the RNA message.
