Scientists have discovered a crucial quality-control mechanism involved in the process of gene transcription that may contribute to major diseases, including cancers, when it fails. The research was done by scientists at the UNC School of Medicine and published in Cell Reports.
In general gene transcription works efficiently and accurately—quite a feat considering DNA’s incredibly tight packaging. How cells wind up the 6 feet of DNA it contains into the nucleus while keeping it carefully organized and indexed largely remains a mystery. What scientists do know is that DNA in our cells is wound into histones and when a cell needs to transcribe a stretch of DNA, the histones and histone chaperones loosen up the nucleosome so that the transcription machinery can access the hidden DNA. When transcription is complete, the nucleosome is put back together to keep DNA firmly wrapped. How this is done is not fully known.
Working in yeast, the UNC team discovered an important piece of this puzzle involving a new function for casein kinase II, and Spt6, which were both known to be involved in transcription, thought their exact roles were unclear.
In the current study, the scientists found that casein kinase II activates Spt6 to allow the chaperone protein to hold down DNA. The enzyme performs this activation by attaching phosphorylation groups onto Spt6. When they reengineered Spt6 to no longer be modified by the kinase, they found that it no longer performed its job well in putting the nucleosome back together. This effect was more pronounced at the starting point of gene transcription.
When Spt6 was reengineered, they observed an increase in transcripts that run from the start of the gene backwards through the gene’s promoter region, rather than downstream. This indicates that casein kinase II’s role is in placing histones back at the beginning of genes to help enforce normal gene transcription.
While this study was done in yeast, all the major players also are present in humans, indicating that these findings could be relevant to humans as well. The discovery could lead to insights into diseases where transcription is interrupted. This is particularly relevant for certain cancers, where abnormal levels of proteins involved in packaging and unpackaging DNA are often present.