Properties of autonomous 3'-->5' exonucleases.
Autonomous 3'-->5' exonucleases (AE) are not bound covalently to DNA polymerases, but they are often included into the replicative complexes. Intracellular AE overproduction in bacteria results in sharp suppression of mutagenesis, whereas inactivation of these enzymes in bacteria and fungi leads to an increase in mutagenesis frequency by 2-3 orders of magnitude. Correction of DNA polymerase errors in vitro occurs after addition of AE to the incubation medium. This correction is clearly manifested under conditions of mutational stress (during induced but not spontaneous mutagenesis), for instance, with an imbalance of dNTPs--error-prone conditions. At equimolar dNTP (error-free conditions), the correction is relatively weak. The gene knockout of both alleles of the major AE gene in mice does not influence spontaneous mutagenesis though a substantial increase could be expected. The frequency of induced mutagenesis has not been yet measured, though the inactivation of AE could increase the frequency of mutagenesis. Complete inactivation of the major AE leads to inflammatory myocarditis and a 5-fold reduction of life span of mice. Dominant heterozygous mutations were found in various loci of the AE gene, which caused the development of Aicardi-Goutieres (autosomal recessive encephalopathy) syndrome, familial chilblain lupus, systemic lupus erythematosus, retinal vasculopathy, and cerebral leukodystrophy. In the nucleus, AE have a corrective function, but after transition into cytoplasm these enzymes destroy aberrant DNA that appears during replication and thereby save the cells from autoimmune diseases. Depending on their intracellular localization, AE carry out various biological functions but employ the same mechanism of the catalyzed reactions.
Krutyakov
V M
VM
Division of Molecular and Radiation Biophysics, Konstantinov St.-Petersburg Nuclear Physics Institute, Russian Academy of Sciences, Gatchina, 188300, Leningrad Region, Russia. krut@omrb.pnpi.spb.ru
D000818:Animals; D001419:Bacteria / Q000201:enzymology / Q000235:genetics; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D004194:Disease / Q000235:genetics; D005092:Exonucleases / Q000235:genetics / Q000378:metabolism*; D005658:Fungi / Q000201:enzymology / Q000235:genetics; D006801:Humans; D051379:Mice
D004259:DNA-Directed DNA Polymerase; D005092:Exonucleases