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Increased somatic mutation burdens in normal human cells due to defective DNA polymerases
- Source :
- Nature Genetics, Nature Genetics, 53(10), 1434-1442. Nature Publishing Group, Robinson, P, H. Coorens, T H, Palles, C, Mitchell, E, Abascal, F, Olafsson, S, Lee, B, Lawson, A, Lee-Six, H, Moore, L, A. Sanders, M, Hewinson, J, J. Campbell, P, Martincorena, I, Tomlinson, I P M & Stratton, M 2021, ' Increased somatic mutation burdens in normal human cells due to defective DNA polymerases ', Nature Genetics . https://doi.org/10.1038/s41588-021-00930-y
- Publication Year :
- 2021
- Publisher :
- Nature Publishing Group US, 2021.
-
Abstract
- Funder: Wellcome Clinical PhD fellowship<br />Funder: Wellcome PhD Studentship<br />Funder: Jean Shank/Pathological Society Intermediate Fellowship<br />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.
- Subjects :
- Premature aging
Adult
Adolescent
DNA polymerase
Somatic cell
Embryonic Development
medicine.disease_cause
Germline
Article
Gastrointestinal cancer
Young Adult
Germline mutation
SDG 3 - Good Health and Well-being
Intestinal Neoplasms
Genetics
medicine
Humans
Germ-Line Mutation
Phylogeny
Aged
DNA Polymerase III
Mutation
POLD1
biology
Genome, Human
Stem Cells
631/443/7
Genomics
DNA Polymerase II
Mutation Accumulation
Middle Aged
631/67/1504
Intestines
Ageing
Mutagenesis
631/208/212
biology.protein
Subjects
Details
- Language :
- English
- ISSN :
- 15461718 and 10614036
- Volume :
- 53
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Nature Genetics
- Accession number :
- edsair.doi.dedup.....c22cab3cc27211c82c6f6f1912a75f1e