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

Hao Dong Li, Ileana Cuevas, Musi Zhang, Changzheng Lu, Md Maksudul Alam, Yang Xin Fu, M. James You, Esra A. Akbay, He Zhang, Diego H. Castrillon

Research output: Contribution to journalArticle

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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? (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.

Original languageEnglish (US)
Pages (from-to)4179-4191
Number of pages13
JournalJournal of Clinical Investigation
Volume128
Issue number9
DOIs
StatePublished - Aug 31 2018

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Neoplasms
Phenotype
DNA-Directed DNA Polymerase
Amino Acid Substitution
DNA Replication
Mutagenesis
Animal Models
Fibroblasts
Alleles
Genome
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load. / Li, Hao Dong; Cuevas, Ileana; Zhang, Musi; Lu, Changzheng; Alam, Md Maksudul; Fu, Yang Xin; You, M. James; Akbay, Esra A.; Zhang, He; Castrillon, Diego H.

In: Journal of Clinical Investigation, Vol. 128, No. 9, 31.08.2018, p. 4179-4191.

Research output: Contribution to journalArticle

Li, Hao Dong ; Cuevas, Ileana ; Zhang, Musi ; Lu, Changzheng ; Alam, Md Maksudul ; Fu, Yang Xin ; You, M. James ; Akbay, Esra A. ; Zhang, He ; Castrillon, Diego H. / Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 9. pp. 4179-4191.
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