Every human cell relies on a protein complex called cohesin to loop its DNA into organised structures, but exactly how this looping is switched on and off remains unknown. This matters because when cohesin or its regulators malfunction, the consequences are severe. Faulty gene regulation, DNA instability, and diseases such as cancer and Cornelia de Lange Syndrome—a rare developmental disorder—can result. Errors during meiosis, the cell division that produces eggs and sperm, can also cause age-related genetic disorders or infertility. Current knowledge cannot explain how cohesin’s activity is controlled, leaving a gap in understanding these conditions. This project is fundamental science. The team will combine structural biology, biochemistry, and cell-based experiments to determine how the protein WAPL, reversible acetylation, and the DNA-binding protein CTCF regulate cohesin’s removal from DNA. Success would reveal the molecular mechanics behind genome organisation. Because this is curiosity-driven research, no immediate clinical application exists. However, similar fundamental work on protein complexes has previously unlocked drug targets for cancer and developmental disorders. A clearer picture of cohesin regulation could eventually guide diagnostics or therapies for the diseases linked to its dysfunction.
View original technical description
Cohesin is an essential protein complex that is best known for its role in ensuring chromosomes segregate correctly during cell division. However, cohesin also has structural and regulatory roles in many other genome-related processes, including controlling gene expression, repairing DNA damage and facilitating DNA recombination. Despite its importance, we still don’t fully understand how cohesin works in these processes. One way cohesin shapes the genome is by forming loops of DNA, creating so-called topologically associated domains (TADs). These loops help bring different parts of the genome together, enabling them to interact and perform their functions. Cohesin forms these loops through a process called loop extrusion, where it structures the DNA into loops until stopped by specific proteins, such as CTCF, or until it is removed by another protein called WAPL. When cohesin or its associated proteins are mutated it can lead to various diseases. These include faulty gene regulation, DNA instability, and diseases such as cancer and Cornelia de Lange Syndrome—a rare developmental disorder. Cohesin dysregulation during meiosis can also cause chromosome segregation errors, leading to age-related genetic disorders or infertility. This project aims to uncover how cohesin is regulated to perform its various roles in the genome. We will focus on understanding how cohesin turnover is regulated by WAPL, reversible acetylation and interaction with cellular ligands such as CTCF. We will combine advanced structural, biochemical and cell-based approaches to to determine how cohesin turnover is regulated and how it contributes to essential processes like gene regulation and chromosome maintenance. Our research will advance basic science and reveal new insights into the causes of genetic diseases, cancer, and infertility and contribute to the development of new treatments and diagnostic tools, ultimately benefiting healthcare.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know