Rules of engagement: How DNA remodelers shape mitotic chromosomes
Despite their microscopic size, each one of our cells contains two meters of DNA tightly packaged within its nucleus. During the cell’s “daily life”, however, genes must be accessible for expression. A balanced interplay of molecular motors is necessary to ensure that the DNA is always in just the right shape.
One motor, a protein complex called cohesin, pulls individual DNA strands loose, forming loops that bring together specific genes and their regulatory sequences to facilitate gene expression. During cell division, however, these loose DNA threads risk tangling or even breaking, which would cause genetic errors in the daughter cells. To mitigate this risk, another protein complex, called condensin, reshapes and compacts the DNA into tighter structures, the mitotic chromosomes, at the onset of cell division.
Although scientists understand the general roles of both cohesin and condensin, how these complexes interact when they meet one another along the DNA is so far unknown. An international research team recently defined the “rules of engagement” that govern the interplay between cohesin and condensin during the critical transition into cell division. The study, carried out by Anton Goloborodko at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, William Earnshaw at the Institute of Cell Biology of the University of Edinburgh, Job Dekker at the UMass Chen Medical School and Howard Hughes Medical Institute and Leonard Mirny at the Massachusetts Institute of Technology, was published in Science on April 11th.
To investigate how cohesin and condensin interact with each other, the researchers first studied how each complex binds to the DNA during the different stages of cell division, and how the absence of either cohesin or condensin affects chromosome structure during cell division.
Using high-resolution optical and electron microscopes and advanced genomics, the scientists observed that condensin binding to the DNA is essential to remove cohesin-mediated DNA loops. Based on their findings, the team formulated and tested different theories about how condensin could interact with cohesin. “We used advanced, physics-based simulations to test how different interaction scenarios influence DNA folding,” explains Anton Goloborodko. “Using these simulations, we could determine which theory best aligns with the changes in DNA structure we observe in the lab.”
The researchers discovered that, at the onset of cell division, condensin binds to the DNA and moves along it, displacing any cohesins that stand in its path. The release of cohesins from the DNA disassembles cohesin-formed DNA loops, enabling condensin to tightly pack DNA for cell division.
Notably, cohesin complexes also play a critical role in physically holding sister chromatids – identical copies of a chromosome produced during DNA replication – together before the chromatids are passed into the separate daughter cells during cell division. Surprisingly, the team found that condensin can tell apart this specific type of cohesin. Indeed, when condensin meets this type of cohesin, it does not remove it from the DNA but instead bypasses this cohesin, thereby ensuring that the sister chromatids continue to be held together.
Lastly, the researchers asked what happens when two condensin complexes encounter each other along the DNA. Their simulations revealed that when condensins meet each other, they stall and form tight loops essential for packaging mitotic chromosomes.
The findings provide new insights into how molecular motors shape DNA structure. “Over the past decade, the community, including us, have understood how condensins and cohesins actively reshape DNA. Our latest research shows how they interact and collaborate to build iconic X-shaped chromosomes seen during cell division,” explains Anton Goloborodko. The study also highlights the value of multi-disciplinary approaches for studying and modeling molecular interactions. “This discovery was made possible by a decade-long collaboration between four labs who have contributed their different expertise,” Goloborodko reflects. “Our shared passion for chromosome biology brought us together into a close-knit and highly productive team.”