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- Title
Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load.
- Authors
Hao-Dong Li; Cuevas, Ileana; Musi Zhang; Changzheng Lu; Alam, Md Maksudul; Yang-Xin Fu; You, M. James; Akbay, Esra A.; He Zhang; Castrillon, Diego H.; Li, Hao-Dong; Zhang, Musi; Lu, Changzheng; Fu, Yang-Xin; Zhang, He
- Abstract
Mutations underlie all cancers, and their identification and study are the foundation of cancer biology. We describe what we believe to be a novel approach to mutagenesis and cancer studies based on the DNA polymerase ε (POLE) ultramutator phenotype recently described in human cancers, in which a single amino acid substitution (most commonly P286R) in the proofreading domain results in error-prone DNA replication. We engineered a conditional PoleP286R allele in mice. PoleP286R/+ embryonic fibroblasts exhibited a striking mutator phenotype and immortalized more efficiently. PoleP286R/+ mice were born at Mendelian ratios but rapidly developed lethal cancers of diverse lineages, yielding the most cancer-prone monoallelic model described to date, to our knowledge. Comprehensive whole-genome sequencing analyses showed that the cancers were driven by high base substitution rates in the range of human cancers, overcoming a major limitation of previous murine cancer models. These data establish polymerase-mediated ultramutagenesis as an efficient in vivo approach for the generation of diverse animal cancer models that recapitulate the high mutational loads inherent to human cancers.
- Subjects
GENETIC load; DNA polymerases; MUTAGENESIS; POLYMERASE chain reaction; CANCER immunology
- Publication
Journal of Clinical Investigation, 2018, Vol 128, Issue 9, p4179
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI122095