Having it both ways: transcription factors that bind DNA and RNA

Abstract

Multifunctional proteins challenge the conventional 'one protein-one function' paradigm. Here we note apparent multifunctional proteins with nucleic acid partners, tabulating eight examples. We then focus on eight additional cases of transcription factors that bind double-stranded DNA with sequence specificity, but that also appear to lead alternative lives as RNA-binding proteins. Exemplified by the prototypic Xenopus TFIIIA protein, and more recently by mammalian p53, this list of transcription factors includes WT-1, TRA-1, bicoid, the bacterial sigma(70) subunit, STAT1 and TLS/FUS. The existence of transcription factors that bind both DNA and RNA provides an interesting puzzle. Little is known concerning the biological roles of these alternative protein-nucleic acid interactions, and even less is known concerning the structural basis for dual nucleic acid specificity. We discuss how these natural examples have motivated us to identify artificial RNA sequences that competitively inhibit a DNA-binding transcription factor not known to have a natural RNA partner. The identification of such RNAs raises the possibility that RNA binding by DNA-binding proteins is more common than currently appreciated.

Figure 1

Schematic depiction of 5S rRNA autoregulation that is formally possible because of the ability of Xenopus TFIIIA to bind both 5S rRNA and the dsDNA encoding it. The 5S rRNA gene is indicated as duplex DNA. In the absence of free TFIIIA (trapezoid), the gene is not transcribed (OFF). Free TFIIIA leads to DNA binding and the assembly of an active complex that recruits RNA polymerase III (ON). Accumulation of 5S rRNA has the potential to titrate levels of free TFIIIA, inhibiting transcription activation.

Figure 2

Molecular structure of a portion of TFIIIA bound to dsDNA. The six N-terminal zinc fingers of TFIIIA are shown in this rendering of the crystal structure (17). No high resolution structure of TFIIIA with 5S rRNA is available. (A) Side view of the complex. Protein (cyan backbone trace) N-terminus is at the right. DNA atoms are indicated as spheres of conventional colors (white, carbon; blue, nitrogen; red, oxygen; gold, phosphorus). (B) View of the complex from the N-terminus of the protein.

Figure 3

Schematic model for genetic and biochemical regulation of C.elegans tra-1 and tra-2. (A) Genetic regulatory relationship (26). (B) Biochemical model for post-transcriptional regulation of tra-2 mRNA localization by TRA-1 protein (25).

Figure 4

Protein biochemistry and putative regulatory interactions of p53. (A) p53 protein domains. AD, activation domain; PRD, proline-rich SH3-binding domain; TET, tetramerization domain; NLS, nuclear localization sequence; P, phosphorylation sites. (B) Examples of genes regulated by p53, and their relationships to DNA damage control and cellular responses.

Figure 5

Natural and artificial nucleic acid ligands for human NF-κB. (A) Strong NF-κB recognition sequence in dsDNA, derived from the HIV-1 LTR promoter. (B) Predicted secondary structure of in vitro-selected RNA aptamer that competes with dsDNA for NF-κB binding (66). (C) Predicted secondary structure of the 31-nt core domain of the selected RNA aptamer.