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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Vydané v:	Nature genetics Ročník 53; číslo 10; s. 1434 - 1442
Hlavní autori:	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.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Nature Publishing Group US 01.10.2021 Nature Publishing Group
Predmet:	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
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-021-00930-y