A simple but profound mutation in mouse DNA polymerase ε drives tumorigenesis
Thomas A. Kunkel
Thomas A. Kunkel
Published August 20, 2018
Citation Information: J Clin Invest. 2018;128(9):3754-3756. https://doi.org/10.1172/JCI123021.
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Commentary

A simple but profound mutation in mouse DNA polymerase ε drives tumorigenesis

Abstract

Over 40 years ago, Loeb and colleagues proposed that errors in DNA replication produce a mutator phenotype that is involved in generating the multiple mutations required for tumor development. In this issue of the JCI, Li, Castrillon, and colleagues describe a mouse model containing a single base change in the gene encoding replicative DNA polymerase ε (POLE) that mimics the “ultramutator” phenotype recently reported in many human tumors. Their seminal accomplishment validates Loeb’s hypothesis and the use of mutational signatures to understand the origins and potentially the treatment of human tumors, and it offers an exciting opportunity to further explore the mechanisms responsible for normal DNA replication fidelity and their perturbations.

Authors

Thomas A. Kunkel

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Figure 1

X-ray crystal structure of DNA polymerase ε.

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X-ray crystal structure of DNA polymerase ε. X-ray crystal structure of ...
X-ray crystal structure of the 142-kDa N-terminal region of the catalytic subunit of yeast DNA polymerase ε (10). Yeast proline 301 is homologous to human proline 286, which is highlighted in green. The catalytic residues for the 3′ exonuclease activity are shown in red. They are located 38.2 Å away from the polymerase active site. See text for further descriptions.