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Topoisomerase 1 Regulates Gene Expression in Neurons through Cleavage Complex-Dependent and -Independent Mechanisms

Angela M Mabb1,2, Jeremy M Simon1, Ian F King1

  • 1Department of Cell Biology and Physiology, UNC Neuroscience Center, Carolina Institute for Developmental Disabilities, The University of North Carolina, Chapel Hill, North Carolina, United States of America.

Plos One
|May 28, 2016
PubMed

Insights

Topoisomerase 1 (TOP1) inhibitors like topotecan impact neuronal gene expression more than TOP1 deletion. This study differentiates TOP1 cleavage complex-dependent and -independent gene regulation mechanisms.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • Topoisomerase 1 (TOP1) inhibitors form covalent complexes (TOP1cc) on DNA, impeding transcription and replication.
  • Previous research indicated topotecan affects long gene expression and Ube3a allele silencing in neurons.

Purpose of the Study:

  • To investigate the overlap between TOP1cc-dependent and -independent gene regulation in neurons.
  • To compare the effects of topotecan treatment with TOP1 deletion on neuronal gene expression.

Main Methods:

  • Utilized Top1 conditional knockout mice, Top1 knockdown, and CRISPR-Cas9 for Top1 deletion.
  • Employed TOP1 catalytic inhibitors lacking TOP1cc formation and a TOP1 mutation (T718A) stabilizing TOP1cc's.
  • Analyzed gene expression changes in response to various TOP1 manipulation strategies.

Main Results:

  • Topotecan treatment altered significantly more genes than Top1 deletion, including long neuronal genes and immediate early genes.
  • Topotecan also induced unsilencing of the paternal Ube3a allele, consistent with previous findings.
  • Topotecan demonstrated a more pronounced effect on neuronal transcription compared to Top1 deletion.

Conclusions:

  • Topotecan exerts a stronger influence on neuronal transcription than simple Top1 deletion.
  • The study delineates both TOP1cc-dependent and -independent mechanisms contributing to gene expression regulation in neurons.

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