Increased Somatic Mutation Burdens in Normal Human Cells Due to Defective DNA Polymerases

Overview

Journal Nat Genet

Specialty Genetics

Date 2021 Oct 1

PMID 34594041

Citations 69

Authors

Philip S Robinson

Tim H H Coorens

Claire Palles

Emily Mitchell

Federico Abascal

Sigurgeir Olafsson

Bernard C H Lee

Andrew R J Lawson

Henry Lee-Six

Luiza Moore

Mathijs A Sanders

James Hewinson

Lynn Martin

Claudia M A Pinna

Sara Galavotti

Raheleh Rahbari

Peter J Campbell

Inigo Martincorena

Ian Tomlinson

Michael R Stratton

Affiliations

Soon will be listed here.

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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