Activators with Enzymatic Activities

Although eukaryotic activators themselves generally contain no enzymatic activities, recent studies challenge this generalization. A group of activators, which belong to the family of Eyes absent (Eya), play important roles in the development of multiple tissues and organs including the eye, kidney and muscle (Epstein and Neel, 2003; Rebay et al., 2005). Recent studies show that Eya proteins, which are non-DNA binding activators, contain phosphatase activities (Li et al., 2003; Rayapureddi et al., 2003; Tootle et al., 2003). It is currently not fully understood what substrates these phosphatases work on and how they specifically contribute to the transcription activation process. Numerous co-factors and components in the transcription machinery contain various enzymatic activities that play critical roles in transcription regulation (Shi and Shi, 2004; Sims et al., 2004b). Therefore, the presence of enzymatic activities in activators may not fundamentally change our way of thinking about transcription. Nevertheless, the identification of enzyme-containing activators establishes a new paradigm of increased complexity in transcription regulation.

Concluding Remarks

I would like to end our discussion by returning to the issue introduced at the beginning of this chapter, i.e., a typical activator contains two important functions, DNA binding and activation. Why, then, do activators have to bind DNA, or for non-DNA binding activators, interact with other DNA-binding proteins? This question touches the very heart of the activation process. DNA binding brings an activator closer to the promoter, its action site, thus effectively increasing its local concentration for the promoter. This in turn leads to more efficient, localized interactions between the activator bound at the enhancer and the transcription machinery bound at the promoter. According to the recruitment model, such localized interactions help recruit the transcription machinery to the promoter. Activator-recruited chromatin remodeling/modifying complexes also exert greater, local effects on DNA accessibility (than untargeted complexes do) to facilitate the assembly of the transcription machinery at the promoter. For genes that are activated through other mechanisms, e.g., elongation, the rate-limiting steps also respond to local stimulation more favorably than untargeted signals.

The relatively weak interactions between activators and components of the transcription machinery represent a critical means to achieve specificity in activation: these interactions (or their effects) may only occur efficiently when the enhancer (to which activators bind) and the promoter (to which the transcription machinery binds) are linked. As discussed already, there are mechanisms that can facilitate long-distance communications between enhancers and promoters. Interestingly, some of these and/or additional mechanisms may also play roles in facilitating a rare class of communications that occur between enhancers and promoters on separate chromosomes (Dorsett, 1999; Duncan, 2002; Muller and Schaffner, 1990). It should be reminded that transcription regulation is not restricted to activation. Genes are also subject to repression and silencing. Similar to activation, repression is also facilitated by targeted, local (or regional) interactions, only to achieve the opposite outcome of reducing transcription levels. Understanding gene regulation requires considerations of the integration of transcriptional activation and repression.


I would like to thank members of my lab for discussions. Research in this lab is supported by grants from the NSF, NIH, AHA and DOD. Support from the NSFC is also acknowledged.

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