Do you know: DNA damage can go unrepaired for years, changing our view of mutations
in 2025
While most known types of DNA damage are fixed by our cells’ internal DNA repair mechanisms, some types of DNA damage avoid repair and can persist for decades, new research shows. This means that the damage has many chances to generate harmful mutations, which can lead to cancer.
Scientists from the Wellcome Sanger Institute and their collaborators analyzed family trees of hundreds of single cells from several individuals. The team assembled these family trees from shared mutation patterns between the cells, indicating a common ancestor.
Researchers have uncovered unexpected mutational inheritance patterns in the trees, indicating that some DNA damage remains unrepaired. In the case of blood stem cells, this can be for two or three years.
The research, published today (January 15) i Naturechanges the way we think about mutations, and has implications for understanding the development of various cancers.
During our lifetime, each of the cells in our body accumulates genetic errors in the genome, called somatic mutations. These can be the result of harmful environmental exposures, such as smoking, as well as the daily chemistry that occurs in our cells.
DNA damage is different from mutation. While a mutation of one of the four standard DNA bases (A, G, T or C) is in the wrong place, like a spelling mistake, DNA damage is a chemical change to the DNA, like a smudged letter unrecognizable . DNA damage can lead to the genetic sequence being misread and copied during a cell – known as DNA replication – and this introduces permanent mutations that can contribute to the development of cancers. However, the DNA damage itself is usually recognized and quickly repaired by repair mechanisms in our cells.
If researchers can better understand the causes and mechanisms of mutations, they may be able to intervene and slow or remove them.
In a new study, Sanger Institute scientists and their collaborators analyzed data in the form of a family tree of hundreds of individual cells from individuals. Families are built from genome-wide patterns of mutations that are shared between cells — for example, cells that share many mutations share and are closely related to a recent common ancestor.
The researchers compiled seven published sets of these gene trees, called somatic phylogenies. The dataset included 103 phylogenies from 89 individuals1which include blood stem cells, bronchial epithelial cells and liver cells.
The team discovered unexpected mutational inheritance patterns in the family trees, showing that some DNA damage can persist unrepaired through multiple rounds of cell division. This was particularly evident in blood stem cells, where 15 to 20 percent of mutations were the result of a specific type of DNA damage that lasts for an average of two to three years, and in some cases longer.
This means that it can make a different mistake during cell division, each time the cell tries to copy the damaged DNA, resulting in different mutations from a single source of DNA damage. Importantly, this creates multiple chances of harmful mutations that can lead to cancer. Researchers point out that although this type of DNA damage is rare, its persistence over the years means it can cause as many mutations as more common DNA damage.
Overall, these findings change the way researchers think about mutations, and have implications for the development of cancer.
Dr Michael Spencer Chapman, first author from the Wellcome Sanger Institute and Barts Cancer Institute, said: “With these family trees, we can link the relationships of hundreds of cells from one person back to conception, which means that trace us back through conception. divisions that each cell has gone through. It is these large, novel data sets that led to the unexpected finding that certain types of DNA damage can persist for a long time without repair. with you you don’t always know what you’ll find until you look;
Emily Mitchell, an author from the Wellcome Sanger Institute, the Wellcome-MRC Cambridge Stem Cell Institute and the University of Cambridge, said: “When we explored blood stem cell family trees in particular, we found a specific type of DNA damage that results in around 15. to 20 per cent of the mutations in these cells, and they can last for several years It is not clear why this process is only found in blood stem cells and not other healthy tissues to investigate what the actual damage As we continue to better understand the causes of mutations, we may one day be able to intervene and remove them.”
Lead author Dr Peter Campbell, formerly of the Wellcome Sanger Institute and now Chief Scientific Officer at Quotient Therapeutics, said: “We have identified types of DNA damage that manage to escape our DNA repair mechanisms and persist in the genome for days, months, or sometimes these results do not match what scientists previously thought about the fundamentals of how mutations are found for the research community and the design of future studies.”