Structural insight on processivity, human disease and antiviral drug toxicity

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Y Whitney Yin1

  • 1University of Texas at Austin, Austin, TX 78712, USA. whitney.yin@cm.utexas.edu

Current Opinion in Structural Biology
|December 28, 2010
PubMed

Insights

Mitochondrial DNA polymerase gamma (Pol γ) resembles T7 DNA polymerase, making it vulnerable to antiviral drugs. This review examines how these drugs cause toxicity by inhibiting Pol γ, impacting organelle DNA replication.

Area of Science:

  • Mitochondrial DNA replication
  • Drug-induced toxicity
  • Structural biology

Background:

  • DNA polymerase gamma (Pol γ) is essential for mitochondrial DNA synthesis.
  • Human Pol γ shares structural similarities with bacteriophage T7 DNA polymerase.
  • This structural resemblance confers susceptibility to certain antiviral agents.

Purpose of the Study:

  • To review recent structural and biochemical studies on Pol γ.
  • To elucidate the mechanisms of Pol γ-mediated antiviral drug toxicity.
  • To understand the implications for organelle DNA synthesis.

Main Methods:

  • Structural analysis of human Pol γ.
  • Biochemical assays to assess enzyme activity and inhibition.
  • Review of existing literature on drug interactions with Pol γ.

Main Results:

  • Pol γ's structural homology to T7 DNA polymerase is a key factor in its drug susceptibility.
  • Antiviral drugs targeting HIV reverse transcriptase and HCV RNA polymerase can inhibit Pol γ.
  • This inhibition can lead to mitochondrial dysfunction and toxicity.

Conclusions:

  • Understanding Pol γ's structure-function relationship is crucial for predicting and mitigating antiviral drug toxicity.
  • Further research into Pol γ inhibition mechanisms can inform the development of safer antiviral therapies.
  • Mitochondrial toxicity is a significant concern with certain antiviral drug regimens.

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