Phenotype-based identification of mouse chromosome instability mutants

Naoko Shima, Suzanne A. Hartford, Ted Duffy, Lawriston A. Wilson, Kerry J. Schimenti, John C. Schimenti

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

There is increasing evidence that defects in DNA double-strand-break (DSB) repair can cause chromosome instability, which may result in cancer. To identify novel DSB repair genes in mice, we performed a phenotype-driven mutagenesis screen for chromosome instability mutants using a flow cytometric peripheral blood micronucleus assay. Micronucleus levels were used as a quantitative indicator of chromosome damage in vivo. Among offspring derived from males mutagenized with the germline mutagen N-ethyl-N-nitrosourea (ENU), we identified a recessive mutation conferring elevated levels of spontaneous and radiation- or mitomycin C-induced micronuclei. This mutation, named chaos1 (chromosome aberration occurring spontaneously 1), was genetically mapped to a 1.3-Mb interval on chromosome 16 containing Polq, encoding DNA polymerase θ. We identified a nonconservative mutation in the ENU-derived allele, making it a strong candidate for chaos1. POLQ is homologous to Drosophila MUS308, which is essential for normal DNA interstrand crosslink repair and is unique in that it contains both a helicase and a DNA polymerase domain. While cancer susceptibility of chaos1 mutant mice is still under investigation, these data provide a practical paradigm for using a forward genetic approach to discover new potential cancer susceptibility genes using the surrogate biomarker of chromosome instability as a screen.

Original languageEnglish (US)
Pages (from-to)1031-1040
Number of pages10
JournalGenetics
Volume163
Issue number3
StatePublished - Mar 1 2003

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    Shima, N., Hartford, S. A., Duffy, T., Wilson, L. A., Schimenti, K. J., & Schimenti, J. C. (2003). Phenotype-based identification of mouse chromosome instability mutants. Genetics, 163(3), 1031-1040.