Every time a cell divides, it must accurately copy and distribute its DNA between two new cells. However, in some cases, chromosomes do not fully separate, leaving behind thin strands of DNA known as DNA bridges that connect the two newly formed cells.
These fragile structures can be vulnerable to damage and, if not properly managed, can have severe consequences for genome stability. Researchers from King's, in collaboration with research teams at the University of Utah and biotechnology company Altos Labs, have now revealed how cells protect themselves from this threat.
Published in Nature Structural & Molecular Biology , the study shows that ESCRT-III proteins, previously known for helping cells reshape and repair membranes, have an unexpected role in protecting DNA bridges during cell division.
During cell division, a safety mechanism called the NoCut checkpoint helps delay the final stages of division when DNA bridges are present. The researchers found that this delay allows ESCRT-III proteins to move to the DNA bridges, where they form a protective coating around the exposed DNA and help prevent damage.
Although DNA bridges are rare in healthy cells, research has linked them to genome instability and some early events associated with cancer development. While the study does not directly demonstrate a link between this mechanism and cancer development, it provides new insight into how cells protect themselves from DNA damage events that have previously been associated with genome instability and disease.
Juan Martin-Serrano, Professor of Viral Cell Biology at King's and co-senior author of the study, said: "The discovery came from an unexpected observation. We saw ESCRT proteins binding to DNA but didn't understand why. After more than 20 years studying these proteins, I never imagined we would uncover this completely new role for them. There is still much more to understand, and our next steps will be to investigate how these DNA bridges form and what enables them to protect the genome.
To study these events at the molecular level, the team used cryo-electron microscopy to determine the structure of the ESCRT/DNA complex. Advanced live-cell microscopy allowed them to watch cells divide in real time. Researchers created specialised cell lines containing fluorescently labelled proteins, enabling them to track DNA and ESCRT proteins as they moved inside living cells.
Because DNA bridges occur infrequently, the researchers used two approaches to study them. They first analysed large numbers of cells to identify naturally occurring DNA bridges. They also temporarily blocked the activity of a protein involved in separating DNA during cell division, increasing the number of DNA bridges available for detailed analysis.
Dr James Glover, co-first author of the study, completed his undergraduate degree, master's and PhD at King's, with his doctoral research carried out in Professor Martin-Serrano's laboratory through the Medical Research Council Doctoral Training Partnership (MRC DTP). He is now continuing his research career internationally as a postdoctoral researcher at the University of California, Berkeley.
Reflecting on the significance of the discovery, Dr Glover said: "When we think about cell division, we often imagine the textbook picture of one cell dividing into two cells with DNA being perfectly distributed. But in reality, many complications can happen as those cells separate.
"What we've discovered is that ESCRT proteins can come in and protect DNA bridges, preventing them from causing damage. The fact that a family of proteins known for remodelling membranes can also protect DNA is such an unexpected and exciting discovery.
The study was supported by the Wellcome Trust, the Biotechnology and Biological Sciences Research Council (BBSRC), and the Medical Research Council (MRC) Doctoral Training Partnership (DTP).
