While most recognized forms of DNA damage are repaired by the cell’s intrinsic repair systems, recent studies indicate that some types can go unrepaired and linger for years. This extended presence allows for multiple opportunities to create dangerous mutations, which may lead to cancer.
While most recognized forms of DNA damage are repaired by the cell’s intrinsic repair systems, recent studies indicate that some types can go unrepaired and linger for years. This extended presence allows for multiple opportunities to create dangerous mutations, which may lead to cancer.
Researchers from the Wellcome Sanger Institute and their colleagues examined the family trees of numerous single cells from various individuals. They constructed these family trees based on patterns of shared mutations, suggesting connections among the cells’ common ancestors.
The researchers discovered unexpected patterns related to mutation inheritance within these family trees, revealing that some DNA damage remains unrepaired for extended periods. For blood stem cells, this can last from two to three years.
This research, published today (15 January) in Nature, alters our understanding of mutations and holds significant implications for our comprehension of different types of cancer development.
Throughout our lives, all cells in our body accumulate genetic mistakes in their DNA known as somatic mutations. These errors can arise from harmful environmental factors like smoking as well as normal cellular processes.
It’s crucial to distinguish between DNA damage and mutations. A mutation refers to one of the four DNA bases (A, G, T, or C) being incorrectly placed, akin to a spelling error. In contrast, DNA damage involves chemical changes to the DNA that may resemble an unclear or smeared letter. Such damage can lead to errors during DNA reading and replication in cell division, resulting in permanent mutations that may spur cancer development. However, the body typically identifies and quickly repairs this damage using its cellular repair systems.
If scientists can gain a clearer understanding of what causes mutations, they may find ways to intervene to slow or eliminate them.
In a recent study, scientists from the Sanger Institute and collaborators analyzed data comprising family trees of hundreds of single cells from individuals. These trees were built from patterns of shared mutations across the genome — for example, if multiple cells share many mutations, they likely descended from a common ancestor cell.
The researchers gathered seven previously published sets of these family trees, collectively called somatic phylogenies. The dataset included 103 phylogenies from 89 individuals1, covering blood stem cells, bronchial epithelial cells, and liver cells.
The team observed surprising patterns of mutation inheritance in the family trees. They discovered that specific types of DNA damage can remain unrepaired through many cell divisions, particularly within blood stem cells, where 15 to 20 percent of mutations stemmed from damage that lingers for an average of two to three years, and sometimes even longer.
This persistence means that during cell division, each time the cell tries to replicate the damaged DNA, it may make different mistakes, resulting in multiple mutations from a single instance of DNA damage. Significantly, this creates numerous opportunities for harmful mutations that could contribute to the onset of cancer. The researchers noted that while these kinds of DNA damages are infrequent, their prolonged existence over years can lead to as many mutations as those caused by more common DNA damage.
Ultimately, these findings significantly alter the perspective of researchers regarding mutations and have important implications for cancer research.
Dr. Michael Spencer Chapman, the first author from the Wellcome Sanger Institute and Barts Cancer Institute, remarked: “With these family trees, we can trace the relationships of hundreds of cells from one individual back to conception, allowing us to follow the divisions each cell has undergone. This innovative dataset has led us to the surprising realization that some forms of DNA damage can remain unaddressed for extended periods. This study exemplifies exploratory science; you never know what you may uncover until you look—staying curious is crucial.”
Emily Mitchell, a co-author from the Wellcome Sanger Institute, Wellcome-MRC Cambridge Stem Cell Institute, and the University of Cambridge, added: “While examining blood stem cell family trees, we found a specific type of DNA damage responsible for about 15 to 20 percent of the mutations in these cells, lasting several years. It remains unclear why this phenomenon is found only in blood stem cells and not in other healthy tissues. Understanding that this DNA damage can persist opens new avenues for investigating its nature. As we further our understanding of mutation causes, we may one day be able to mitigate or eliminate them.”
Dr. Peter Campbell, the lead author who previously worked at the Wellcome Sanger Institute and is now the Chief Scientific Officer at Quotient Therapeutics, stated: “We have pinpointed DNA damage types that evade our cellular repair mechanisms, persisting in the genome for days, months, or sometimes even years. These results challenge the established views on how mutations are acquired. This paradigm shift adds a new layer to our understanding of mutations and is vital for the research community in shaping future studies.”
