Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load.

摘要: Mutations underlie all cancers, and their identification study are the foundation of cancer biology. We describe what we believe to be a novel approach mutagenesis studies based on DNA polymerase e (POLE) ultramutator phenotype recently described in human which single amino acid substitution (most commonly P286R) proofreading domain results error-prone replication. engineered conditional PoleP286R allele mice. PoleP286R/+ embryonic fibroblasts exhibited striking mutator immortalized more efficiently. mice were born at Mendelian ratios but rapidly developed lethal cancers diverse lineages, yielding most cancer-prone monoallelic model date, our knowledge. Comprehensive whole-genome sequencing analyses showed that driven by high base rates range overcoming major limitation previous murine models. These data establish polymerase-mediated ultramutagenesis as an efficient vivo for generation animal models recapitulate mutational loads inherent cancers.