A New Coactivator Function for Zac1's C₂H₂ Zinc Finger DNA-Binding Domain in Selectively Controlling PCAF Activity

Abstract

The generally accepted paradigm of transcription by regulated recruitment defines sequence-specific transcription factors and coactivators as separate categories that are distinguished by their abilities to bind DNA autonomously. The C₂H₂ zinc finger protein Zac1, with an established role in canonical DNA binding, also acts as a coactivator. Commensurate with this function, p73, which is related to p53, is here shown to recruit Zac1, together with the coactivators p300 and PCAF, to the p21^Cip1 promoter during the differentiation of embryonic stem cells into neurons. In the absence of autonomous DNA binding, Zac1's zinc fingers stabilize the association of PCAF with p300, suggesting its scaffolding function. Furthermore, Zac1 regulates the affinities of PCAF substrates as well as the catalytic activities of PCAF to induce a selective switch in favor of histone H4 acetylation and thereby the efficient transcription of p21^Cip1. These results are consistent with an authentic coactivator function of Zac1's C₂H₂ zinc finger DNA-binding domain and suggest coactivation by sequence-specific transcription factors as a new facet of transcriptional control.

ACKNOWLEDGMENTS

We thank members of the Molecular Neuroendocrinology group and Osborne Almeida for discussions on the manuscript.

Funding was provided by the Deutsche Forschungsgemeinschaft (SP 386/5-1 to D.S.) and the European Union (Crescendo LSHM-CT-2005-018652).

A.H. and D.S. conceived the study, designed the experimental strategy, and analyzed the data. D.S. wrote the paper, performed the cotransfection studies, and constructed part of the plasmids. A.H. prepared and performed the pull-down assays, RT-PCR experiments, ChIP assays, siRNA treatments, IBs and coimmunoprecipitations, in vitro HAT assays, and transfection studies.