Non-base-contacting residues enable kaleidoscopic evolution of metazoan C2H2 zinc finger DNA binding

• Published in: Genome Biology 2017-09, Vol.18 (1), p.167-167, Article 167
• Main Authors: Najafabadi, Hamed S, Garton, Michael, Weirauch, Matthew T, Mnaimneh, Sanie, Yang, Ally, Kim, Philip M, Hughes, Timothy R
• Format: Article
• Language: English
• Subjects: Binding sites; Deoxyribonucleic acid; Diversification; DNA; Evolution; Fungi; Genomes; Preferences; Proteins; Taxonomy; Transcription factors; Vocabularies & taxonomies; Zinc finger proteins
• ISSN: 1474-760X; 1474-7596; 1474-760X
• DOI: 10.1186/s13059-017-1287-y

The C2H2 zinc finger (C2H2-ZF) is the most numerous protein domain in many metazoans, but is not as frequent or diverse in other eukaryotes. The biochemical and evolutionary mechanisms that underlie the diversity of this DNA-binding domain exclusively in metazoans are, however, mostly unknown. Here, we show that the C2H2-ZF expansion in metazoans is facilitated by contribution of non-base-contacting residues to DNA binding energy, allowing base-contacting specificity residues to mutate without catastrophic loss of DNA binding. In contrast, C2H2-ZF DNA binding in fungi, plants, and other lineages is constrained by reliance on base-contacting residues for DNA-binding functionality. Reconstructions indicate that virtually every DNA triplet was recognized by at least one C2H2-ZF domain in the common progenitor of placental mammals, but that extant C2H2-ZF domains typically bind different sequences from these ancestral domains, with changes facilitated by non-base-contacting residues. Our results suggest that the evolution of C2H2-ZFs in metazoans was expedited by the interaction of non-base-contacting residues with the DNA backbone. We term this phenomenon "kaleidoscopic evolution," to reflect the diversity of both binding motifs and binding motif transitions and the facilitation of their diversification.