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Genetics, Vol. 163, 1031-1040, March 2003, Copyright © 2003

Phenotype-Based Identification of Mouse Chromosome Instability Mutants

Naoko Shimaa, Suzanne A. Hartforda, Ted Duffya, Lawriston A. Wilsona, Kerry J. Schimentia, and John C. Schimentia
a The Jackson Laboratory, Bar Harbor, Maine 04609

Corresponding author: John C. Schimenti, 600 Main St., Bar Harbor, ME 04609., jcs{at}jax.org (E-mail)

Communicating editor: D. KINGSLEY

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 {theta}. 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.




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