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Molecular and Cellular Biology, December 2004, p. 10381-10389, Vol. 24, No. 23
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.23.10381-10389.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Mouse Genomic Instability Mutation chaos1 Is an Allele of Polq That Exhibits Genetic Interaction with Atm

Naoko Shima,{dagger} Robert J. Munroe,{dagger} and John C. Schimenti*

The Jackson Laboratory, Bar Harbor, Maine

Received 21 July 2004/ Returned for modification 10 August 2004/ Accepted 19 August 2004

chaos1 (for chromosome aberrations occurring spontaneously 1) is a recessive mutation that was originally identified in a phenotype-based screen for chromosome instability mutants in mice. Mutant animals exhibit significantly higher frequencies of spontaneous and radiation- or mitomycin C-induced micronucleated erythrocytes, indicating a potential defect in homologous recombination or interstrand cross-link repair. The chaos1 allele was genetically associated with a missense mutation in Polq, which encodes DNA polymerase {theta}. We demonstrate here that chaos1 is a mutant allele of Polq by using two genetic approaches: chaos1 mutant phenotype correction by a bacterial artificial chromosome carrying wild-type Polq and a failed complementation test between chaos1 and a Polq-disrupted allele generated by gene targeting. To investigate the potential involvement of Polq in DNA double-strand break repair, we introduced chaos1 into an Atm (for ataxia telangiectasia mutated)-deficient background. The majority (~90%) of double-homozygous mice died during the neonatal period. Surviving double mutants exhibited synergistic phenotypes such as severe growth retardation and enhanced chromosome instability. However, remarkably, double mutants had delayed onset of thymic lymphoma, significantly increasing life span. These data suggest a unique role of Polq in maintaining genomic integrity, which is probably distinctive from the major homologous recombination pathway regulated by ATM.

* Corresponding author. Present address: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, 9th Fl. Vet. Research Tower, Ithaca, NY 14853. Phone: (607) 253-3636. Fax: (607) 253-3851. E-mail: jcs92{at}cornell.edu.

{dagger} Present address: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

Molecular and Cellular Biology, December 2004, p. 10381-10389, Vol. 24, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.23.10381-10389.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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