Phenotype-based identification of mouse chromosome instability mutants.

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 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.

• Authors: Naoko Shima, Suzanne A Hartford, Ted Duffy, Lawriston A Wilson, Kerry J Schimenti, John C Schimenti
• Journal: Genetics (Genetics) Vol. 163 Issue 3 Pg. 1031-40 (Mar 2003) ISSN: 0016-6731 [Print] United States
• PMID: 12663541 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Mutagens
• DNA polymerase theta
• DNA-Directed DNA Polymerase
• Ethylnitrosourea

Topics

• Animals
• Chromosome Mapping
• Chromosomes (drug effects, genetics)
• Crosses, Genetic
• DNA Damage
• DNA Repair (genetics)
• DNA-Directed DNA Polymerase (genetics)
• Ethylnitrosourea (toxicity)
• Female
• Male
• Mice
• Mice, Inbred C3H (genetics)
• Mice, Inbred C57BL (genetics)
• Micronucleus Tests
• Models, Genetic
• Molecular Sequence Data
• Mutagenesis
• Mutagens (toxicity)
• Phenotype
• Transcription, Genetic