Zinc finger 4 negatively controls the transcriptional activator Fzf1 in .

Fzf1 is a transcription factor containing five zinc fingers (ZFs). It regulates the expression of at least five downstream genes, including , , 3, and , by recognizing a consensus sequence, CS2, found in these gene promoters. These gene products are involved in cellular responses to various chemical stresses. For example, encodes a sodium sulfite efflux protein that confers sulfite resistance. However, the underlying molecular mechanism through which Fzf1 responds to chemical stress and coordinates target gene activation remains elusive. Interestingly, several mutations in the fourth ZF (ZF4) of Fzf1 have previously been reported to confer either sulfite resistance or elevated basal-level expression of , indicating that ZF4 negatively impacts Fzf1 activity. Since ZF4 is dispensable for CS2 binding in vitro, we hypothesized that ZF4 is a negative regulator of Fzf1 and that chemically induced Fzf1-regulated gene expression occurs via de-repression. All five genes examined were cross-induced by corresponding chemicals in an Fzf1-dependent manner, and all three ZF4 mutations and a ZF4 deletion conferred increased basal-level expression and -dependent sulfite resistance. A ZF4 deletion did not alter the target DNA binding, consistent with the observed codominant phenotype. These observations collectively reveal that Fzf1 remains inactive by default at the target promoters and that its activation is at least partially achieved by self-derepression through chemical modification and/or a conformational change.