Increased somatic mutation burdens in normal human cells due to defective DNA polymerases
Open accessPublished version of a preprint
Abstract
Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE / POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE / POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE / POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE / POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.
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Cancer research suggests that colibactin causes DNA damage early after exposure.
“cancer research suggests that colibactin causes DNA damage early after exposure [157, 158].”
From Selection, Comparative Genomics, and Potential Probiotic Features of Escherichia coli 5C, a pks-Negative Strain Isolated from Healthy Infant Donor Feces (2026) · cites this paper as [158]
The Results (Mutational signatures; page unavailable) describe colibactin as a mutagenic product and say a signature likely due to it is predominantly acquired during childhood. This supports a link to DNA mutations, but the paper does not establish that damage occurs early after exposure; childhood acquisition is not a measure of time since exposure. (LLM, conf=0.82)
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References 85 · Cited by 173
- Authors
- Robinson, P. S., Coorens, T. H. H., Palles, C., Mitchell, E., Abascal, F., Olafsson, S., Lee, B. C. H., Lawson, A. R. J., Lee-Six, H., Moore, L., Sanders, M. A., Hewinson, J., Martin, L., Pinna, C. M. A., Galavotti, S., Rahbari, R., Campbell, P. J., Martincorena, I., Tomlinson, I., & Stratton, M. R.
- Affiliations
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- University of Birmingham (GB)
- Queen Mary Hospital (CN)
- Erasmus MC (NL)
- Edinburgh Cancer Research (GB)
- Corresponding author
- Tomlinson, Ian
- Stratton, Michael R.
- ORCID
- Venue
- Nature Genetics
- Published
- 2021-09-30
- Volume
- 53
- Issue
- 10
- Pages
- 1434-1442
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC8492474
- OpenAlex
- W3202536610
- Cited by
- 173
- References
- 85
- Citations by year
- 2026: 15 · 2025: 38 · 2024: 33 · 2023: 40 · 2022: 36 · 2021: 10 · 2020: 1
- FWCI
- 11.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Genetics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo
- Apollo (cc-by)
- Funders
- Wellcome Clinical PhD fellowship
- Wellcome PhD Studentship
- Jean Shank/Pathological Society Intermediate Fellowship
- Cancer Research UK (C66259/A27114)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- somatic mutation burden, DNA polymerase proofreading, mutational signatures, embryonic development, sperm mutagenesis, aging, cancer susceptibility, DNA replication
- MeSH terms
- Adolescent, Adult, Aged, DNA Polymerase II, DNA Polymerase III, Humans, Intestinal Neoplasms, Intestines, Middle Aged, Phylogeny, Stem Cells, Genome, Human, Mutagenesis, Germ-Line Mutation, Embryonic Development, Young Adult
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