Publication highlights

An international group of researchers from the Crick, Imperial College London, Waseda University and the Cancer Institute of the Japanese Foundation for Cancer Research have redrawn the idea of chromosome shape, finding that they’re not always stable X-shaped structures but are constantly in flux as cell division takes place. They live-imaged chromosomes over time, observing that they become continuously shorter and thicker, and that they are aiming for a 'final roundness' - a ratio of length and width that's the most physically stable. Using computer simulations, they showed that longer chains reach far longer to reach a stable length, suggesting that they aren't in a steady state at cell division, whereas shorter chains reach a steady state almost straight away. The team conclude that the length of time chromosomes spend in mitosis dictates whether they will all reach a final shape or not.

Sister chromatids of DNA are held together by a ring-shaped protein complex called cohesin, and scientists have long pondered how the DNA-copying machinery manages to navigate genetic strands while encountering cohesin rings. After finding that the replisome can travel through the cohesin ring, a multidisciplinary team of researchers at the Crick investigated sister chromatid cohesion in more detail. They often observed that cohesin hugged just a single DNA copy after replication, and that a structure called the 'cohesin loader' appears to intervene and bring the second chromatid into the ring. They also showed that sometimes more cohesin molecules are used, bringing together the chromatids in a two-step process involving additional cohesin molecules to those present before replication.

Sister chromatids of DNA are held together by a ring-shaped protein complex called cohesin, and scientists have long pondered how the DNA-copying machinery manages to navigate genetic strands while encountering cohesin rings. A multidisciplinary team of researchers at the Crick use a biological reconstitution method to explore this. When they loaded cohesin onto DNA and added the replisome, in some cases they witnessed the replisome travelling through the ring. Additionally, the more replisome components they added, the more efficiently the complex passed through the rings, despite its increased size. Finally, the team showed that the components responsible for helping the replisome pass through the cohesin ring where DNA polymerase enzymes. In a complimentary paper, they also showed that there are other ways for the replisome to bypass cohesin rings.

In healthy cell division, the replicated DNA forms sister chromatids that must remain connected until separation later in the process. It’s only then that X-shaped chromosomes must be segregated symmetrically: each sister chromatid (one half of the X) is pulled to the opposite edges of the dividing cell by microtubules - protein filaments that generate force – to give rise to two daughter cells with an equal amount of genetic material. A ring-shaped protein called cohesin physically links sister chromatids and, like an elastic band, resists the forces generated by microtubules. Not only is the absence of cohesion lethal, but mutations in it can lead to cancer and incurable developmental disorders.

In this research by the Molodtsov and Uhlmann groups, the force that the cohesin complex can withstand is revealed. Using optical tweezers, the researchers pulled apart the DNA molecules tied by cohesin, showing that one cohesin ring is capable of embracing two DNAs and can resist up to 20 piconewtons of force, and when it breaks, it always opens at its weakest point: the hinge domain. These findings reveal that 40 cohesins are sufficient to oppose the tension generated in mitosis, whilst larger forces release the sisters. For the first time, this work lifts the veil on cohesin’s physical properties, bringing us closer to understanding how it is dysregulated in disease.

Faithful chromosome segregation to daughter cells involves an additional critical feature, namely that the two newly synthesised products of DNA replication, the sister chromatids, stay connected to one another. This process, known as sister chromatid cohesion, allows the cell division machinery to recognise replication products for faithful segregation into daughter cells during cell divisions. Sister chromatid cohesion is mediated by cohesin, a ring-shaped protein complex that topologically entraps the two sister DNAs. The process requires modification—in this case acetylation—of conserved cohesin lysine residues. The Uhlmann lab, in collaboration with John Diffley’s group, has now shown how this process is linked to DNA replication. Reconstitution in a test tube of replication-coupled cohesin acetylation reveals that flaps or nicks, transient DNA structures which form during DNA replication, are transient molecular clues that direct cohesin acetylation next to where cohesin likely co-entraps the replication products. These important results give the first detailed explanation of how DNA replication is linked to sister chromatid cohesion establishment.