Mutated Cohesin Throws DNA Splicing out of Whack, Resulting in Cancer

The protein complex cohesin is fundamental to the cell division process, as it holds sister chromatids tightly together in a ringlike structure before a cell physically splits. But now researchers at the National Cancer Institute (NCI) have uncovered that the protein complex has another function, too—one that can answer questions that have mystified cancer researchers for decades.

A study published Wednesday (March 1) in Science Advances suggests that cohesin regulates alternative splicing—the phenomenon when coding regions of a gene are combined in different ways during transcription, allowing the gene to code for multiple distinct proteins —which is important for a range of cellular processes, including cell development and death. This also implicates cohesin in the development of acute myeloid leukemia (AML) and other types of cancer, which can grow and progress when alternative splicing runs rampant.

“In AML primary patient cells, there are cohesin mutations and, in turn, you see changes in splicing,” says study coauthor Dinah Singer, an immunologist at the NCI. These dysregulations in alternative splicing have been shown to play an important role in cancer by contributing to tumor initiation and progression. “Having this insight opens up the possibility to maybe reverse the growth phenotype and, down the line, pursue new avenues for treatment,” she adds.

Up to 95 percent of protein-coding genes, also known as multi-exon genes, undergo alternative splicing. This process is crucial for changing genomic instructions into functional proteins with different roles. But when there is a splicing mutation, nucleoids at the splice site are inserted or deleted. These splicing mutations are linked to a range of genetic alterations in AML, with 20 percent of the cases also exhibiting a cohesin mutation. This led the researchers to investigate whether cohesin mutations are associated with alternative splicing.

See “Alternative Splicing Provides a Broad Menu of Proteins for Cells

In the study, Dinah and her colleagues depleted cohesin in human colorectal cancer cell lines through inducible degrading of RAD21, a central component of the cohesin complex. When they studied the effect of this depletion on splicing patterns using RNA sequencing, they found that splicing was significantly affected in cell lines with cohesin mutations compared to controls.

The researchers also studied the role of cohesin in AML by using independent, publicly available RNA sequencing datasets of patient samples. The first set of samples selected for analysis had cohesin mutations only but no splicing mutations. The second set included samples with splicing mutations only but no cohesin mutations. A third group of samples was used for control and had no cohesin or splicing mutations.

When the group compared the splicing patterns of the different sets of samples, they found that unique patterns of splicing were only observed in samples with cohesin mutations. Together, these findings suggest that cohesin regulates alternative splicing, and cohesin mutations contribute to the progression of AML and other cancers.

“This new function of cohesin is very exciting,” says Kajsa Paulsson, a medical geneticist who specializes in cancer genomics at Lund University Cancer Centre in Sweden but was not involved in the study. Cohesin mutations are associated with a wide range of common cancer types, she explains, but the underlying mechanism has remained a mystery, thwarting scientists seeking to develop targeted treatments.

“This is a big step towards understanding the effect of these mutations,” she adds. “But we still can’t be sure that’s the only thing they’re doing.”

Dinah and her colleagues agree, and they’re interested in finding out the extent to which cohesin mutations contribute to the progression of cancer, as well as answering other important questions like how cohesin regulates gene expression.

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