Genome Integrity Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA.
Address correspondence to: Thomas A. Kunkel, Genome Integrity Structural Biology Laboratory, Mail Drop E3-01, National Institute of Environmental Health Sciences, NIH, 111 T.W. Alexander Drive, Research Triangle Park, North Carolina 27707, USA.Phone: 919.541.2644; Email: firstname.lastname@example.org.
First published August 20, 2018 - More info
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.
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