Phenotype-based identification of mouse chromosome instability mutants.
Genetics
; 163(3): 1031-40, 2003 Mar.
Article
em En
| MEDLINE
| ID: mdl-12663541
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
/
Mutagênese
/
Mapeamento Cromossômico
/
Cromossomos
/
Reparo do DNA
/
Etilnitrosoureia
/
Camundongos Endogâmicos C57BL
/
Camundongos Endogâmicos C3H
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
Idioma:
En
Revista:
Genetics
Ano de publicação:
2003
Tipo de documento:
Article