After a decade of work, scientists have completed a molecular model of the human spliceosome, an incredibly complex cellular machine. When an active gene is expressed in a cell, it is transcribed into a messenger RNA molecule, which has to be processed and edited in various ways, or spliced, before it can be interpreted, or translated into a protein by the cell. It's thought that over 90 percent of human genes are modified by the spliceosome, and errors in the splicing process have been associated with many different disorders, including many types of cancer. The work has been reported in Science.
This study has revealed new details of the spliceosome complex that might be targeted with novel medications to treat disease.
"The layer of complexity we've uncovered is nothing short of astonishing. We used to conceptualize the spliceosome as a monotonous but important cut and paste machine," noted senior study author and Research Professor Juan Valcárcel of the Center for Genomic Regulation (CRG) and ICREA. "We now see it as a collection of many different flexible chisels that allow cells to sculpt genetic messages with a degree of precision worthy of marble sculpting grandmasters from antiquity. By knowing exactly what each part does, we can find completely new angles to tackle a wide spectrum of diseases."
There are around 20,000 genes that encode for protein. But gene sequences can often be spliced or modified in different ways, such that one gene sequence might encode for a variety of proteins, depending on how the sequences are spliced. Some research has suggested that there are about 100,000 different proteins found in the human body, which are made from about 20,000 genes.
The spliceosome itself is composed of 150 different proteins, plus five small RNA molecules. In this study, the researchers examined the activity of 305 human genes that are related to the spliceosome.
This effort, which was performed in a cancer cell culture model, indicated that various parts of the spliceosome have different regulatory functions, each of which carries out specific jobs that can determine how genetic sequences are edited and processed. The spliceosome has a significant effect on human protein expression.
One part of the spliceosome can choose what part of an RNA sequence is edited out, while another ensures that cut is made at the right place. There is another portion that helps regulate the different parts of the spliceosome. The spliceosome complex was found to be interconnected, with disruptions in one portion having significant effects on other parts of the complex.
"Their reliance on a highly interconnected splicing network is a potential Achilles' heel [in cancer cells] we can leverage to design new therapies, and our blueprint offers a way of discovering these vulnerabilities," said Valcárcel.
The molecular map of the spliceosome is now publicly available, so scientists can determine where splicing errors may be arising in patient cells.
"Current splicing treatments are focused on rare diseases, but they are just the tip of the iceberg," noted co-corresponding study author Dr. Malgorzata Rogalska. "The blueprint we've developed paves the way for entirely new therapeutic approaches. It's only a matter of time."
Sources: Center for Genomic Regulation, Science