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- Title
Phenotype-Based Identification of Mouse Chromosome Instability Mutants.
- Authors
Shima, Naoko; Hartford, Suzanne A.; Duffy, Ted; Wilson, Lawriston A.; Schimenti, Kerry J.; Schimenti, John C.
- 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-ethylN-nitrosourea (ENU), we identified a recessive mutation conferring elevated levels of spontaneous and radiation- or mitomycin G-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 homologons 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 tinder 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.
- Subjects
CHROMOSOMES; MICE; MUTAGENESIS; NUCLEOLUS; GENETICS
- Publication
Genetics, 2003, Vol 163, Issue 3, p1031
- ISSN
0016-6731
- Publication type
Article
- DOI
10.1093/genetics/163.3.1031