"Naked" FACT is unstable.

A central dogma in biology states that the flow of biological information is from DNA to RNA to proteins. This model originally predicted that any changes in the levels of mRNA would lead to concomitant changes in protein levels. However, it appeared that the relationships between the levels of mRNAs and the levels of proteins they encode, particularly in eukaryotes, are not that straightforward. In mammals, less than half of all genes reveal a positive correlation between mRNA and protein levels and the correlations of transcripts and proteins varies depending on the cellular location and biological function of the gene. Clearly, in eukaryotes post-transcriptional control of gene expression plays an important role in modulating protein levels. Eukaryotic mRNAs do not exist in cells as naked polynucleotides, but rather are represented by messenger ribonucleoprotein complexes mRNPs. mRNA binding proteins may affect almost every aspect of mRNP metabolism from transport to localization, translation and turnover. In addition, protein levels are greatly influenced by co- and post-translational modifications. While the impact of proteins on mRNA stability is well known, what has been unclear thus far is whether proteins can be stabilized by interactions with mRNA(s). Evidence in support of the later has been very scarce.

In the current issue of Cell Cycle, Safina et al. presented an unusual finding suggesting that mRNAs may stabilize proteins against degradation. This paper revealed an unprecedented interplay between expression and stability of the two subunits of the Facilitate Chromatin Transcription (FACT) chromatin remodeling complex and the mRNAs encoding the FACT two subunits. FACT is a heterodimer of the 80 kDa, so-called Structure-specific recognition protein 1 (SSRP1), and the 140 kDa, so-called Suppressor of Ty16 (SPT16) protein. FACT complex is involved in multiple processes such as DNA replication, DNA repair and mRNA elongation. Mechanisms controlling FACT cellular levels are of fundamental interest to the field of cancer biology, since FACT has been found to be frequently upregulated in cancers, particularly in poorly differentiated aggressive tumors. Moreover, suppression of FACT expression in tumor cells has been shown to lead to tumor cell death. Therefore, FACT represents an attractive target for therapeutic intervention. Mechanisms controlling FACT cellular levels have been the focus of the study by Safina et al. This study has been triggered by an observation that SSRP1 and SPT16 protein levels decline upon induction of cellular differentiation (or senescence) and that a similar decline of both proteins can be observed upon RNAi-mediated knockdown of, quite surprisingly, either of SSRP1 or SPT16 mRNAs. These results suggested that there is a crosstalk between SSRP1 mRNA and SPT16 protein levels and vise-versa. Immunoprecipitation experiments revealed that SSRP1 and SPT16 mRNAs are present in the FACT complex and further showed that this association is specific. This observation allowed the authors to suggest that the presence of the SSRP1 and SPT16 mRNAs in FACT may play a certain role in either promoting the assembly of the complex and/or its stabilization against degradation. Through a set of elegant experiments, the authors further demonstrated that neither mRNA is required for FACT complex assembly however upon binding to the FACT the mRNAs increase the stability of FACT’s protein components. In addition, binding of SSRP1 and SPT16 mRNAs to the FACT complex appeared to increase the efficiency of their translation. In the absence of FACT complex, both mRNAs are unstable and inefficiently translated making reactivation of FACT complex unlikely. The authors put forward a model in which mRNAs and particularly SSRP1 mRNA is suggested to play a key role in FACT complex stabilization. Thus, FACT complex is stable, when mRNAs are present, but rapidly degrades, when the mRNA levels drop. These findings are unique and novel. However, further detailed understanding of the exact mechanism(s) leading to FACT stabilization upon mRNA(s) binding is required. It would be of interest to map mRNA-protein binding interfaces and delineate the exact region(s) in both mRNA and protein components of the FACT responsible for FACT stabilization. Nevertheless, this is one of the first reports revealing such an unusual role of mRNA in protein stabilization. This article adds to our understanding of the multifaceted roles of RNAs in cellular homeostasis and opens up new avenues in the study of the FACT complex.