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The role of SOS and flap processing in microsatellite instability in Escherichia coli
1Génétique Microbienne, Institut National de la Recherche Agronomique, Domaine de Vilvert, 78352 Jouy en Josas Cedex, France.
Abstract:
Mutations affecting mismatch repair result in elevated frequencies of microsatellite length alteration in prokaryotes and eukaryotes. However, the finding that microsatellite instability is found often in cells with a functional mismatch repair system prompted a search for other factors of tract alteration. In the present report, we show that, in Escherichia coli, poly(AC/TG) tracts are destabilized by mutations that induce SOS. These observations may have implications for eukaryotic cells because recent results suggest the existence of a mammalian SOS response analogous to that in prokaryotes. In addition, a defect in the 5'-3' exonuclease domain of DNA polymerase I, homologous to the mammalian FEN1 and the yeast RAD27 nucleases, leads to a marked increase in repeat expansions characteristic of several genetic disorders. Finally, we found that the combination of a proofreading defect with mismatch repair deficiency results in extreme microsatellite instability.
Insights
Microsatellite instability can occur even with functional mismatch repair. DNA polymerase I defects and SOS induction in E. coli destabilize microsatellite tracts, impacting genetic disorder research.
Area of Science:
- Molecular Biology
- Genetics
- Microbiology
Background:
- Mismatch repair deficiency is a known cause of microsatellite instability.
- Microsatellite instability is frequently observed in cells with functional mismatch repair, suggesting other contributing factors.
Purpose of the Study:
- To investigate additional factors contributing to microsatellite tract alteration beyond mismatch repair.
- To explore the role of SOS induction and DNA polymerase I in microsatellite instability.
Main Methods:
- Utilized Escherichia coli as a model organism.
- Introduced mutations to induce SOS response.
- Examined the effect of defects in the 5'-3' exonuclease domain of DNA polymerase I.
Main Results:
- SOS-inducing mutations destabilize poly(AC/TG) tracts in E. coli.
- Defects in DNA polymerase I's exonuclease domain significantly increase repeat expansions.
- Combined proofreading and mismatch repair defects lead to extreme microsatellite instability.
Conclusions:
- SOS response and DNA polymerase I function are critical factors in microsatellite stability.
- Findings in E. coli may have implications for understanding mammalian SOS response and genetic disorders.
- Synergistic effects of proofreading and mismatch repair deficiencies exacerbate microsatellite instability.