Gene-Targeted Mice Lacking the Trex1 (DNase III) 3′→5′ DNA Exonuclease Develop Inflammatory Myocarditis

Abstract

TREX1, originally designated DNase III, was isolated as a major nuclear DNA-specific 3′→5′ exonuclease that is widely distributed in both proliferating and nonproliferating mammalian tissues. The cognate cDNA shows homology to the editing subunit of the Escherichia coli replicative DNA polymerase III holoenzyme and encodes an exonuclease which was able to serve a DNA-editing function in vitro, promoting rejoining of a 3′ mismatched residue in a reconstituted DNA base excision repair system. Here we report the generation of gene-targeted Trex1^−/− mice. The null mice are viable and do not show the increase in spontaneous mutation frequency or cancer incidence that would be predicted if Trex1 served an obligatory role of editing mismatched 3′ termini generated during DNA repair or DNA replication in vivo. Unexpectedly, Trex1^−/− mice exhibit a dramatically reduced survival and develop inflammatory myocarditis leading to progressive, often dilated, cardiomyopathy and circulatory failure.

We thank Ashfaq Gilkar and Mahrokh Nohadani for histopathology, Christine Saunders and Russell Sanderson for work with MEF cell lines, Tania Jones for sister chromatid exchange analyses, Michael Bradburn for assistance with statistical analysis, Michael Mitchell for database searches, and Mary Ann Haskings, Anthony Iglesias, Barbara Rudling, Del Watling, Stephen Wilson, and Cheryl Young for technical assistance. We thank Susumu Nishimura for facilitating a long-term visit of M.M. to the Clare Hall laboratories.

This work was supported by Cancer Research UK.