Much of spontaneous mutagenesis in Escherichia coli is due to error-prone DNA repair: implications for spontaneous carcinogenesis

1981 ◽  
Vol 2 (9) ◽  
pp. 863-872 ◽  
Author(s):  
Neil J. Sargentini ◽  
Kendric C. Smith
Keyword(s):  
Escherichia Coli ◽  
Dna Repair ◽  
Spontaneous Mutagenesis ◽  
Spontaneous Carcinogenesis

The lacI Gene as a Target for Mutation in Transgenic Rodents and Escherichia coli

Genetics ◽  
1998 ◽  
Vol 148 (4) ◽  
pp. 1441-1451
Author(s):  
Johan G de Boer ◽  
Barry W Glickman
Keyword(s):  
Escherichia Coli ◽  
Dna Repair ◽  
Dna Binding ◽  
Transgenic Animals ◽  
Single Copy ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Large Database ◽  
Deletion Mutations ◽  
Laci Gene

Abstract The lacI gene has been used extensively for the recovery and analysis of mutations in bacteria with various DNA repair backgrounds and after exposure to a wide variety of mutagens. This has resulted in a large database of information on mutational mechanisms and specificity of many mutagens, as well as the effect of DNA repair background on mutagenicity. Most importantly, knowledge about the mutational sensitivity of the lacI gene is now available, yielding information about mutable nucleotides. This popularity and available knowledge resulted in the use of the lacI gene in transgenic rodents for the study of mutagenesis in mammals, where it resides in ~40 repeated copies. As the number of sequenced mutations recovered from these animals increases, we are able to analyze the sites at which mutations have been recovered in great detail and to compare the recovered sites between bacteria and transgenic animals. The nucleotides that code for the DNA-binding domain are nearly saturated with base substitutions. Even after determining the sequences of ~10,000 mutations recovered from the animals, however, new sites and new changes are still being recovered. In addition, we compare the nature of deletion mutations between bacteria and animals. Based on the nature of deletions in the animals, we conclude that each deletion occurs in a single copy of the gene.

Evidence for two recA genes mediating DNA repair in Bacillus megaterium

Microbiology ◽  
2005 ◽  
Vol 151 (3) ◽  
pp. 775-787 ◽  
Author(s):  
Hannes Nahrstedt ◽  
Christine Schröder ◽  
Friedhelm Meinhardt
Keyword(s):  
Escherichia Coli ◽  
Dna Repair ◽  
Mitomycin C ◽  
Bacillus Megaterium ◽  
Functional Complementation ◽  
Homologous Gene ◽  
Gene Products ◽  
Null Mutant ◽  
Promoter Regions ◽  
Increased Sensitivity

Isolation and subsequent knockout of a recA-homologous gene in Bacillus megaterium DSM 319 resulted in a mutant displaying increased sensitivity to mitomycin C. However, this mutant did not exhibit UV hypersensitivity, a finding which eventually led to identification of a second functional recA gene. Evidence for recA duplicates was also obtained for two other B. megaterium strains. In agreement with potential DinR boxes located within their promoter regions, expression of both genes (recA1 and recA2) was found to be damage-inducible. Transcription from the recA2 promoter was significantly higher than that of recA1. Since a recA2 knockout could not be achieved, functional complementation studies were performed in Escherichia coli. Heterologous expression in a RecA null mutant resulted in increased survival after UV irradiation and mitomycin C treatment, proving both recA gene products to be functional in DNA repair. Thus, there is evidence for an SOS-like pathway in B. megaterium that differs from that of Bacillus subtilis.

scholarly journals Synthetic Lethality with the dut Defect in Escherichia coli Reveals Layers of DNA Damage of Increasing Complexity Due to Uracil Incorporation

2008 ◽  
Vol 190 (17) ◽  
pp. 5841-5854 ◽  
Author(s):  
Helen Ting ◽  
Elena A. Kouzminova ◽  
Andrei Kuzminov
Keyword(s):  
Escherichia Coli ◽  
Dna Repair ◽  
Metabolic Pathways ◽  
Synthetic Lethality ◽  
Nucleotide Metabolism ◽  
Genetic Interactions ◽  
Single Defect ◽  
Damage Repair ◽  
Mutant Combination ◽  
Dna Incorporation

ABSTRACT Synthetic lethality is inviability of a double-mutant combination of two fully viable single mutants, commonly interpreted as redundancy at an essential metabolic step. The dut-1 defect in Escherichia coli inactivates dUTPase, causing increased uracil incorporation in DNA and known synthetic lethalities [SL(dut) mutations]. According to the redundancy logic, most of these SL(dut) mutations should affect nucleotide metabolism. After a systematic search for SL(dut) mutants, we did identify a single defect in the DNA precursor metabolism, inactivating thymidine kinase (tdk), that confirmed the redundancy explanation of synthetic lethality. However, we found that the bulk of mutations interacting genetically with dut are in DNA repair, revealing layers of damage of increasing complexity that uracil-DNA incorporation sends through the chromosomal metabolism. Thus, we isolated mutants in functions involved in (i) uracil-DNA excision (ung, polA, and xthA); (ii) double-strand DNA break repair (recA, recBC, and ruvABC); and (iii) chromosomal-dimer resolution (xerC, xerD, and ftsK). These mutants in various DNA repair transactions cannot be redundant with dUTPase and instead reveal “defect-damage-repair” cycles linking unrelated metabolic pathways. In addition, two SL(dut) inserts (phoU and degP) identify functions that could act to support the weakened activity of the Dut-1 mutant enzyme, suggesting the “compensation” explanation for this synthetic lethality. We conclude that genetic interactions with dut can be explained by redundancy, by defect-damage-repair cycles, or as compensation.

scholarly journals Deficiency in Poly(ADP-ribose) Polymerase-1 (PARP-1) Accelerates Aging and Spontaneous Carcinogenesis in Mice

2008 ◽  
Vol 2008 ◽  
pp. 1-11 ◽  
Author(s):  
Tatiana S. Piskunova ◽  
Maria N. Yurova ◽  
Anton I. Ovsyannikov ◽  
Anna V. Semenchenko ◽  
Mark A. Zabezhinski ◽  
...  
Keyword(s):  
Dna Repair ◽  
Life Span ◽  
Soft Tissues ◽  
Telomere Maintenance ◽  
Biological Aging ◽  
Spontaneous Tumors ◽  
Uterine Tumors ◽  
Dna Repair Gene ◽  
Spontaneous Carcinogenesis ◽  
Parp 1

Genetic and biochemical studies have shown that PARP-1 and poly(ADP-ribosyl)ation play an important role in DNA repair, genomic stability, cell death, inflammation, telomere maintenance, and suppressing tumorigenesis, suggesting that the homeostasis of poly(ADP-ribosyl)ation and PARP-1 may also play an important role in aging. Here we show that PARP- mice exhibit a reduction of life span and a significant increase of population aging rate. Analysis of noninvasive parameters, including body weight gain, body temperature, estrous function, behavior, and a number of biochemical indices suggests the acceleration of biological aging in PARP- mice. The incidence of spontaneous tumors in both PARP- and PARP- groups is similar; however, malignant tumors including uterine tumors, lung adenocarcinomas and hepatocellular carcinomas, develop at a significantly higher frequency in PARP- mice than PARP- mice (72% and 49%, resp.; .05). In addition, spontaneous tumors appear earlier in PARP- mice compared to the wild type group. Histopathological studies revealed a wide spectrum of tumors in uterus, ovaries, liver, lungs, mammary gland, soft tissues, and lymphoid organs in both groups of the mice. These results demonstrate that inactivation of DNA repair gene PARP-1 in mice leads to acceleration of aging, shortened life span, and increased spontaneous carcinogenesis.

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