Increased somatic mutation burdens in normal human cells due to defective DNA polymerases

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...

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Published in:Nature genetics Vol. 53; no. 10; pp. 1434 - 1442
Main Authors: Robinson, Philip S., Coorens, Tim H. H., Palles, Claire, Mitchell, Emily, Abascal, Federico, Olafsson, Sigurgeir, Lee, Bernard C. H., Lawson, Andrew R. J., Lee-Six, Henry, Moore, Luiza, Sanders, Mathijs A., Hewinson, James, Martin, Lynn, Pinna, Claudia M. A., Galavotti, Sara, Rahbari, Raheleh, Campbell, Peter J., Martincorena, Iñigo, Tomlinson, Ian, Stratton, Michael R.
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.10.2021
Nature Publishing Group
Subjects:
631/208/212
631/443/7
631/67/1504
Adolescent
Adult
Aged
Agriculture
Animal Genetics and Genomics
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cell division
DNA Polymerase II - genetics
DNA Polymerase III - genetics
DNA polymerases
Embryonic Development - genetics
Gene Function
Gene mutations
Genetic aspects
Genetic research
Genome, Human - genetics
Germ-Line Mutation - genetics
Health aspects
Human Genetics
Humans
Intestinal Neoplasms - pathology
Intestines - pathology
Middle Aged
Mutagenesis - genetics
Phylogeny
Somatic cells
Stem Cells - pathology
Young Adult
United Kingdom
ISSN:1061-4036, 1546-1718, 1546-1718
Online Access:Get full text
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Summary: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. Healthy tissues from individuals with germline mutations in POLE or POLD1 show increased mutational burden, suggesting that normal cells are capable of tolerating high mutation rates.
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ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-021-00930-y