Researchers at Cardiff University have uncovered how a particularly severe form of DNA damage arises - shedding new light on mutation processes that contribute to cancer and inherited genetic conditions.
The study, led by Dr Greg Ngo and Professor Duncan Baird from Cardiff University's School of Medicine, reveals the mechanism behind chromoanasynthesis, a catastrophic type of chromosome rearrangement that leads to highly complex patterns of mutation.
Dr Ngo, Research Fellow, said: "DNA mutations are a fundamental part of cancer development, disrupting the instructions that normally regulate how cells grow, divide and repair themselves.
"Chromoanasynthesis is one of the most extreme forms of DNA mutation, involving massive, chaotic restructuring of a chromosome — a phenomenon that has been described as 'chromosome rebirth'."
Until now, the biological process driving these mutations had remained unclear.
Using an advanced DNA sequencing technique designed to examine complex changes near the end of chromosomes, known as telomeres, the team demonstrated that these mutations occur when DNA breaks during cell division. Rather than repairing the damage cleanly, dividing cells rely on a repair mechanism that uses only tiny segments of matching DNA to reconnect broken strands.
The researchers discovered that two separate DNA repair systems unexpectedly combine during this process, causing the DNA-copying machinery to jump erratically across the genome. This can result in large sections of DNA being duplicated many times, creating the chaotic patterns characteristic of chromoanasynthesis.
By showing how telomere dysfunction triggers this error-prone repair pathway, we provide a clear explanation for how such dramatic chromosome rearrangements form. Understanding this process is crucial because these events can accelerate cancer development and influence how tumours behave.
The findings offer new opportunities for medical research. By identifying the proteins and pathways involved, scientists may be able to develop drugs that target these mechanisms directly.
The work also opens the door to new diagnostic approaches, including the possibility of detecting these complex mutation signatures in early-stage disease.
We were astonished by the complexity of the mutations we observed. Because we can now induce and study these events in the lab, we have a powerful system to investigate which repair factors are involved and where potential diagnostic hotspots might lie.
Cancer Research UK's director of research and partnerships, Catherine Elliott, said: "We are proud to support this groundbreaking work from Cardiff University, which uncovers a fascinating new understanding of how chaotic chromosome mutations arise.
"These insights into chromoanasynthesis mark an important step forward in our mission to unravel the fundamental biology of cancer.
"By identifying the mechanisms that drive these dramatic genetic changes, this research not only deepens our scientific knowledge but also opens up new possibilities for earlier detection and the development of more targeted treatments. We are delighted to have funded a study with such potential to improve outcomes for people affected by cancer."
The research, Mitotic microhomology-mediated break-induced replication promotes chromoanasynthesis , was published in Nature Communications. The study was funded by Cancer Research UK.
