Researchers have discovered that a single protein, Spt6, has more roles in regulating gene expression than previously understood. Spt6 protein, named transcription elongation factor SPT6, was previously known to maintain chromatin structure during RNA transcription and help reassemble DNA post-transcription. This new study uncovered that Spt6 has multiple specialty roles in mRNA processing including RNA degradation which is important for maintaining just enough transcript in the cells for making the optimal amount of protein. The study, performed at the University of Carolina School of Medicine, was published today in Molecular Cell.
Failure of the gene expression mechanism to produce too much or too little protein can result in diseases, such as cancer. "By revealing and understanding this mechanism, we can start to think about targeting parts of it therapeutically in diseases in which Spt6 isn't working properly," said study senior author Brian D. Strahl, PhD, the Oliver Smithies Investigator, Professor, and Vice Chair in the Department of Biochemistry & Biophysics at UNC-Chapel Hill.
RNA Polymerase II (RNAPII) is the enzyme that copies DNA into RNA and it is known the Spt6 binds RNAPII. In order to understand how Spt6 and RNAPII interact, the team developed a non-binding version of Spt6 and found that it was still able to apply histones back to the DNA, however, many more copies of RNA were present in studies with the mutant version. "It dawned on us that there is more to Spt6 function than just re-wrapping the DNA around histones and facilitating RNA Polymerase copying of DNA," said first author Raghuvar Dronamraju, PhD, research assistant professor in Strahl's lab. The non-binding version had lost some of it’s ability maintain the right amount RNA and too many copies can lead to growth and cell division problems.
Taking a closer look, the research team determined that Spt6 uses its interaction with RNAPII to recruit a protein degradation complex, Ccr4-Not, during the gene expression process. By not binding RNAPII, Spt6 was unable to reach the amount of RNA degradation enzymes needed to maintain the right level of RNA copies.
Overall, the study uncovered new insights into the RNA degradation mechanism and how Spt6 has a key role the process. The findings suggest that Spt6 may not perform its RNA degradation function properly in certain cancers which can result in uncontrolled cell growth. The research team is focusing on how much a poorly functioning Spt6 protein contributes to cancer with the goal of identifying new therapeutic targets.