Prolonged persistence of mutagenic DNA lesions in stem cells

Abstract DNA suffers continual damage leaving a cell with thousands of individual DNA lesions at any given moment1–3. The efficiency of DNA repair means that most known classes of lesion have a half-life of minutes to hours3,4, but whether some DNA damage can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising from 832 DNA lesions that persisted across multiple cell cycles in normal human stem cells from blood, liver and bronchial epithelium5–12. Persistent DNA lesions occurred at increased rates, with distinctive mutational signatures, in donors exposed to tobacco or chemotherapy, suggesting that they can arise from exogenous mutagens. In haematopoietic stem cells, persistent DNA lesions, likely from endogenous sources, generated a characteristic mutational signature, so-called SBS1913; occurred steadily throughout life, including in utero; and endured for 1.5 years on average, with 15% lasting 3+ years. We estimate that a haematopoietic stem cell has, on average, ~4-5 such lesions at any moment in time, half of which will generate a mutation with each cell cycle. Overall, 16% of mutations in blood cells are attributable to SBS19, and similar proportions of driver mutations in blood cancers exhibit this signature. These data imply the existence of a family of DNA lesions, arising from both endogenous and exogenous mutagens, present in low numbers per genome but persisting for months to years, that can generate sizable fractions of cells’ mutation burdens.