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Related Experiment Videos

Extrachromosomal elements in the lower eukaryote Leishmania.

R C Hightower1, L M Ruiz-Perez, M L Wong

  • 1Department of Biochemistry and Biophysics, University of California, San Francisco 94143.

The Journal of Biological Chemistry
|November 15, 1988
PubMed
Summary

Extrachromosomal DNA elements in Leishmania protozoa are amplified and linked to methotrexate resistance. These circular DNA molecules facilitate adaptation to drug selection in Leishmania populations.

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Area of Science:

  • Parasitic protozoology
  • Molecular genetics
  • Drug resistance mechanisms

Background:

  • Wild-type Leishmania populations harbor extrachromosomal DNA (ecDNA) elements.
  • These ecDNA elements are nonhomologous, supercoiled circular DNA molecules originating from different chromosomes.

Purpose of the Study:

  • To investigate the nature and properties of extrachromosomal DNA elements in Leishmania.
  • To explore the relationship between ecDNA and methotrexate (MTX) resistance in Leishmania.

Main Methods:

  • Orthogonal-field-alternation-gel electrophoresis (OFAGE) for DNA detection.
  • Electron microscopy for physical characterization of DNA elements.
  • Drug selection experiments using methotrexate (MTX).

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Main Results:

  • Identified 80-kilobase supercoiled circular ecDNA molecules with inverted repeats in L. major and L. tropica.
  • Observed amplification and copy number fluctuation (undetectable to ~20 copies/cell) of ecDNA.
  • A second amplified DNA homologous to L. major ecDNA emerged in MTX-selected L. tropica.
  • Leishmania with ecDNA showed enhanced adaptation to MTX selection compared to populations lacking amplified DNA.

Conclusions:

  • Extrachromosomal DNA elements in Leishmania are amplified and possess structural features conducive to genetic adaptation.
  • A strong correlation exists between the presence of ecDNA and the development and persistence of MTX resistance in Leishmania.
  • ecDNA likely plays a significant role in the evolutionary adaptation of Leishmania to drug pressure.