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Molecular and Cellular Biology, August 2004, p. 6719-6727, Vol. 24, No. 15
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.15.6719-6727.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Masashi Morita,1,{dagger} Gordon Stamp,2 Peter Robins,1 Anna Dulic,1 Ian Rosewell,1 Geza Hrivnak,1 Graham Daly,1 Tomas Lindahl,1* and Deborah E. Barnes1

Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD,1 Department of Histopathology, Faculty of Medicine, Imperial College, London W12 0NN, United Kingdom2

Received 11 February 2004/ Returned for modification 29 February 2004/ Accepted 1 May 2004

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.

* Corresponding author. Mailing address: Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, United Kingdom. Phone: 44-207-269-3993. Fax: 44-207-269-3819. E-mail: lindahl{at}cancer.org.uk.

{dagger} Present address: Banyu Tsukuba Research Institute, Tsukuba, Ibaraki 300-2611, Japan.

Molecular and Cellular Biology, August 2004, p. 6719-6727, Vol. 24, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.15.6719-6727.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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