Publication highlights

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.

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.

Whole-genome duplication (WGD) is a frequent event in cancer evolution and an important driver of aneuploidy—having an abnormal number of chromosomes. The role of the p53 tumour suppressor in WGD has been enigmatic: p53 can stop aneuploid cells from proliferating, acting as a barrier to WGD, but it can also promote mitotic bypass—a key step in WGD in which replication of DNA is uncoupled from the normal next step of cell division (mitosis).

In tumours containing normal p53, WGD is frequently associated with excessive amounts of the protein cyclin E1. The Diffley lab has now shown that too much cyclin E1 causes replicative stress, which arrests the cell cycle after DNA replication but before the cell divides. p53 then drives a process that promotes mitotic bypass, which would normally be a red flag to the cell, triggering a retreat into the safety of senescence. However, the excess cyclin E overrides senescence, allowing cells to complete endoreduplication. P53 therefore contributes to cancer evolution and hence progression by promoting WGD.

Researchers in the Costa and Diffley labs have used high resolution cryo-electron microscopy techniques to observe replicative helicase activation following loading onto DNA. As a prelude to cell division, the genome must be duplicated, and replicative helicases play a fundamental part in this, unwinding DNA and exposing the single-stranded template for the replicative polymerases. The team characterised the role of the key enzymes involved in selectively activating the replicative helicases at the right time and in the right places on DNA, an important step forward in understanding exactly how DNA replication works in both health and disease.