Diversification of Transcription Factor Paralogs via Noncanonical Modularity in C2H2 Zinc Finger DNA Binding

Abstract

Summary A major challenge in obtaining a full molecular description of evolutionary adaptation is to characterize how transcription factor (TF) DNA binding specificity can change. To identify mechanisms of TF diversification, we performed detailed comparisons of yeast C2H2 ZF proteins with identical canonical recognition residues that are expected to bind the same DNA sequences. Unexpectedly, we found that ZF proteins can adapt to recognize new binding sites in a modular fashion whereby binding to common core sites remains unaffected. We identified two distinct mechanisms, conserved across multiple Ascomycota species, by which this molecular adaptation occurred. Our results suggest a route for TF evolution that alleviates negative pleiotropic effects by modularly gaining new binding sites. These findings expand our current understanding of ZF DNA binding and provide evidence for paralogous ZFs utilizing alternate modes of DNA binding to recognize unique sets of noncanonical binding sites.

Transcription factor–DNA binding: beyond binding site motifs

“…Siggers et al found that certain paralogous yeast C2H2-zf TFs in the Msn2 family recognize a core motif common to all Msn2 family members (5′-AGGGG) as well as TF-specific motifs ( e.g. , 5′-ATAGGR, 5′-AGGNAC), and that recognition of the different motifs evolved modularly [46]. Large-scale studies of TF–DNA binding preferences have shown that recognition of multiple motifs, including those with variable spacing and orientation of motif half-sites, are not uncommon [2,4,6,12,47].…”

“…For example, large-scale B1H assays and structural analyses have shown that in C2H2-zf proteins, residues at the finger–finger interface and the order of fingers within an array frequently influence specificity [48,49]. In particular, adjacent fingers can constrain mutual finger orientation and influence the positioning of specificity-determining residues [46,50]. Residues outside the zinc fingers ( e.g.…”

How do regulatory networks evolve and expand throughout evolution?

“…Promiscuity seems to be a feature inherent to most proteins and enzymes: a large fraction of them have been reported to possess multiple activities [52,53]. Many transcription factors also show variation in DNA binding abilities: they can recognize both a (preferred) motif as well as an additional motif(s) [54,55,56 ].…”

“…Recent studies demonstrate the ability of duplicated transcription factors to diversify and bind a number of different DNA motifs [55,56 ]. A new study focuses on the family of fungal C 2 H 2 Zn-finger transcription factors [56 ].…”

“…A new study focuses on the family of fungal C 2 H 2 Zn-finger transcription factors [56 ]. These proteins can be divided into several 'specificity' groups, each group encompassing proteins with identical canonical DNA-recognition amino acid residues.…”