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Published on: April 10, 2018
Phenotype-based identification of mouse chromosome instability mutants
Naoko Shima1, Suzanne A Hartford, Ted Duffy
1The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
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.
Insights
Researchers identified a new gene, DNA polymerase theta (Polq), crucial for DNA double-strand-break repair. Defects in this repair pathway can lead to chromosome instability and potentially cancer.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Defects in DNA double-strand-break (DSB) repair are linked to chromosome instability and cancer development.
- Identifying novel genes involved in DSB repair is crucial for understanding cancer susceptibility.
Purpose of the Study:
- To identify novel mouse genes involved in DNA double-strand-break repair using a forward genetic screen.
- To investigate the role of DNA polymerase theta (Polq) in maintaining genomic stability.
Main Methods:
- Phenotype-driven mutagenesis screen in mice using a flow cytometric peripheral blood micronucleus assay to detect chromosome instability.
- Genetic mapping of the identified mutation (chaos1) to a specific chromosomal region.
- Sequencing of candidate genes within the mapped interval, including Polq.
Main Results:
- A recessive mutation, chaos1, was identified, causing elevated spontaneous and induced micronuclei levels, indicating chromosome damage.
- The chaos1 mutation was mapped to a 1.3-Mb interval on chromosome 16, containing the Polq gene.
- A nonconservative mutation in the ENU-induced Polq allele strongly implicates it as the cause of chaos1.
- Polq is homologous to Drosophila MUS308, involved in DNA interstrand crosslink repair and possessing helicase and polymerase domains.
Conclusions:
- The study identified a novel mouse mutant (chaos1) with defects in DNA double-strand-break repair, linked to chromosome instability.
- DNA polymerase theta (Polq) is a strong candidate gene for the chaos1 mutation, highlighting its role in maintaining genomic integrity.
- This research provides a valuable forward genetic approach for discovering new cancer susceptibility genes using chromosome instability as a biomarker.
