A two-faced molecule: deciphering cohesin’s dual role
Inside the microscopic cell nucleus resides our genome, a two-meter-long DNA strand meticulously organised in compact chromosomes by cohesin, a protein complex. This molecular architect facilitates DNA interactions throughout the cell cycle, shaping loops within chromosomes and mediating contacts between chromosomes. Scientists in the lab of IMP Scientific Director Jan-Michael Peters have gained unexpected insights into the mechanisms that govern these functions, now published in the journal Molecular Cell.
The traditional depiction of cells as simple spheres, scantily populated by organelles, belies the bustling microscopic metropolis that is our cells' reality. In fact, each cell in our body is peppered with a seemingly chaotic assemblage of microscopic components: from small peptides to large protein complexes, DNA, RNA, lipids, and sugars, confined in organelles or free-floating. For a cell to maintain itself, interactions between these molecules must be finely regulated.
The genome's structure and operation require intricate DNA interactions within cells. During cell division, chromosomes duplicate into sister chromatids, which must stay in close contact until they are ready to be distributed to daughter cells. Cohesin, a protein complex, orchestrates this intimacy. As division approaches, cohesin releases its grip, allowing chromatids to part ways.
Healthy cells demand not only interactions between chromatids but also within DNA molecules. With 23 pairs of chromosomes and two meters of DNA per cell, a strategic arrangement is vital. Here, cohesin shines as a DNA-folding machine. It crafts loops, drawing different segments of a molecule together, arranging the sprawling DNA within the nucleus.
Cohesin’s two roles – mediating contact between and within DNA molecules – fulfil very different functions, and the underlying molecular mechanisms may differ. Postdoc Kota Nagasaka and colleagues, mentored by IMP Scientific Director Jan-Michael Peters, investigated these mechanisms in a study now published in the journal Molecular Cell.
Cohesin’s two vital roles require different mechanisms
Cohesin complexes feature a ring-shaped structure. To keep sister chromatids together, cohesin is thought to open this ring and entrap DNA like a hand would. In 2019, scientists in the team showed that this ring opening doesn’t occur in loop formation, which hinted at different action modes.
In the current study, Nagasaka and colleagues examined a mutated version of cohesin that can form DNA loops, but fails to maintain sister chromatid cohesion.
“The mutant protein we describe has a dysfunctional ring – yet it can still perform one of its two functions: loop formation. It’s a strong piece of evidence that the underlying mechanisms differ,” says first-author Nagasaka.
Although the integrity of cohesin’s ring did not seem crucial for loops to form, another twist emerged. In a normal cell, cohesin complexes stop reeling loops when they encounter CTCF, a DNA-bound protein. In the mutant, they simply wouldn’t stop, rendering loops unstable.
“We were surprised to see that the mutated cohesin didn’t end loop formation where it should. Based on previous studies, we thought that cohesin’s ring didn’t interact with CTCF,” says Nagasaka. “Our hypothesis shifted. We now speculate that cohesin momentarily opens its ring upon approaching CTCF and ensnares DNA. This would contribute to ending the reeling of the DNA loop at the right spot. It could explain how loops can be maintained for long periods of time.”
“This study marks a pivotal step in deciphering cohesin's multifaceted functions. The findings provide a solid foundation for future explorations of the complex molecular choreography that underpins cohesin’s vital roles in the cell,” says Jan-Michael Peters.
Original study
Kota Nagasaka, Iain F. Davidson, Roman R. Stocsits, Wen Tang, Gordana Wutz, Paul Batty, Melanie Panarotto, Gabriele Litos, Alexander Schleiffer, Daniel W. Gerlich and Jan-Michael Peters: “Cohesin mediates DNA loop extrusion and sister chromatid cohesion by distinct mechanisms”. Molecular Cell (2023). DOI: 10.1016/j.molcel.2023.07.024.
Further reading
Research with Jan-Michael Peters
Gene transcription hampers cohesin’s travel along chromosomes