The synthegradases idea was first discussed in Bregman et al. 2011.
In the Discussion of this paper we wrote:
A common theme is emerging whereby some transcription activators (e.g., Rap1p, Rpb4/7, Ccr4p) enhance mRNA decay, in addition to their role in transcription. We propose to name these factors ‘‘synthegradases’’ to emphasize their dual role. Recent studies demonstrated that environmentally induced genes are subject to transcriptional induction that is accompanied by an increase in decay rate of their transcripts (Elkon et al., 2010; Molin et al., 2009; Rabani et al.,2011; Shalem et al., 2008). This counter-intuitive ‘‘counteraction’’ characterizes mainly mRNAs whose levels are shaped by a sharp ‘‘peaked’’ behavior (Rabani et al., 2011; Shalem et al., 2008). The capacity of the synthegradases, like Rap1p, to enhance both mRNA synthesis and decay might serve as a mechanistic basis for this phenomenon. As proposed previously, the combination of enhanced synthesis and decay permits rapid acquisition of a new steady-state level (Shalem et al., 2008). We suspect that the two-arms mechanism of the synthegradases is more responsive to regulatory signals. Specifically, signaling pathways can modulate either the synthetic or the decay function of the synthegradases, thereby fine-tuning the desired steady-state levels, as well as the kinetics with which they are achieved.
Recent comparison between mRNA decay kinetics in two related Saccharomyces species revealed a significant difference in 11% of the orthologous mRNAs. In half of these cases, the different decay was coupled to a difference in transcription. Coupling almost always involves enhancement of both mRNA synthesis and decay or, conversely, repression of both mRNA synthesis and decay (Dori-Bachash et al., 2011). Moreover, some yeast factors (most notably Rpb4p and Ccr4p) seem to have evolved in a manner that either enhances both mRNA synthesis and decay or represses both activities simultaneously. At least 5% of the 3,000 yeast genes examined in this study (that excludes genes encoding ribosomal proteins) is likely to be regulated by synthegradases during optimal proliferation conditions (Dori-Bachash et al., 2011). We suspect that this number is likely to increase upon shifts from optimal to stress conditions and after including the Rap1p-regulated genes. A corollary of the double roles of promoters and synthegradases has evolutionary implications, whereby a single mutation in either a promoter or a synthegradase can affect both mRNA synthesis and decay, which otherwise would require two independent mutations (see also Dahan et al., 2011).
Current work
Using bioinformatics approach, we found a number of proteins that both bind mRNAs and also function as transcription factors or bind transcription. We will select those that, indeed, function as synthegradases (using various criteria). We will then examine whether they share common features and study, in some details, the most interesting ones. Later we will examine which of these synthegradases have functional homolog in human. These homologs are potential targets for drug therapy.