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dc.contributor.authorRobinson, Philip S
dc.contributor.authorCoorens, Tim HH
dc.contributor.authorPalles, Claire
dc.contributor.authorMitchell, Emily
dc.contributor.authorAbascal, Federico
dc.contributor.authorOlafsson, Sigurgeir
dc.contributor.authorLee, Bernard CH
dc.contributor.authorLawson, Andrew
dc.contributor.authorLee-Six, Henry
dc.contributor.authorMoore, Luiza
dc.contributor.authorSanders, Mathijs A
dc.contributor.authorHewinson, James
dc.contributor.authorMartin, Lynn
dc.contributor.authorPinna, Claudia MA
dc.contributor.authorGalavotti, Sara
dc.contributor.authorRahbari, Raheleh
dc.contributor.authorCampbell, Peter J
dc.contributor.authorMartincorena, Iñigo
dc.contributor.authorTomlinson, Ian
dc.contributor.authorStratton, Michael R
dc.date.accessioned2021-11-02T01:28:54Z
dc.date.available2021-11-02T01:28:54Z
dc.date.issued2021-10
dc.identifier.issn1061-4036
dc.identifier.otherPMC8492474
dc.identifier.other34594041
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330179
dc.descriptionFunder: Wellcome PhD Studentship
dc.descriptionFunder: Jean Shank/Pathological Society Intermediate Fellowship
dc.descriptionFunder: Wellcome Clinical PhD fellowship
dc.description.abstractMutation 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.
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1546-1718
dc.sourcenlmid: 9216904
dc.titleIncreased somatic mutation burdens in normal human cells due to defective DNA polymerases.
dc.typeArticle
dc.date.updated2021-11-02T01:28:53Z
prism.endingPage1442
prism.issueIdentifier10
prism.publicationNameNat Genet
prism.startingPage1434
prism.volume53
dc.identifier.doi10.17863/CAM.77621
dcterms.dateAccepted2021-07-28
rioxxterms.versionofrecord10.1038/s41588-021-00930-y
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidRobinson, Philip S [0000-0002-6237-7159]
dc.contributor.orcidCoorens, Tim HH [0000-0002-5826-3554]
dc.contributor.orcidAbascal, Federico [0000-0002-6201-1587]
dc.contributor.orcidLawson, Andrew [0000-0003-3592-1005]
dc.contributor.orcidLee-Six, Henry [0000-0003-4831-8088]
dc.contributor.orcidMoore, Luiza [0000-0001-5315-516X]
dc.contributor.orcidPinna, Claudia MA [0000-0002-5618-7842]
dc.contributor.orcidRahbari, Raheleh [0000-0002-1839-7785]
dc.contributor.orcidCampbell, Peter J [0000-0002-3921-0510]
dc.contributor.orcidMartincorena, Iñigo [0000-0003-1122-4416]
dc.contributor.orcidTomlinson, Ian [0000-0003-3037-1470]
dc.contributor.orcidStratton, Michael R [0000-0001-6035-153X]
dc.identifier.eissn1546-1718
pubs.funder-project-idCancer Research UK (C66259/A27114)
pubs.funder-project-idWellcome Trust (206194)
cam.issuedOnline2021-09-30


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International