Gene-targeted mice lacking the Trex1 (DNase III) 3'-->5' DNA exonuclease develop inflammatory myocarditis.
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.
Morita
Masashi
M
Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, United Kingdom.
Stamp
Gordon
G
Robins
Peter
P
Dulic
Anna
A
Rosewell
Ian
I
Hrivnak
Geza
G
Daly
Graham
G
Lindahl
Tomas
T
Barnes
Deborah E
DE
D000818:Animals; D015139:Blotting, Southern; D002455:Cell Division; D002470:Cell Survival; D004247:DNA / Q000378:metabolism; D004260:DNA Repair; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000502:physiology*; D018390:Gene Targeting; D005838:Genotype; D007249:Inflammation; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D016296:Mutagenesis; D009154:Mutation; D009205:Myocarditis / Q000235:genetics*; D009206:Myocardium / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary; D013950:Thymus Gland / Q000473:pathology; D013997:Time Factors
D018076:DNA, Complementary; D010750:Phosphoproteins; D004247:DNA; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1