Affiliation:
1. The Jackson Laboratory, Bar Harbor, Maine
Abstract
ABSTRACT
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 θ. 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.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
124 articles.
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