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Anticancer DNA intercalators cause p53-dependent mitochondrial DNA nucleoid re-modelling

N Ashley1, J Poulton

  • 1Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Level 3, Women's Centre, John Radcliffe Hospital, Headington, Oxford, UK. Neil.Ashley@clin-pharm.ox.ac.uk

Oncogene
|August 18, 2009
PubMed

Insights

Anticancer drugs like doxorubicin (DXR) enter mitochondria, causing DNA damage. A mitochondrial response remodels DNA, but some damage leads to mitochondrial DNA depletion and potential drug toxicity.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Anticancer drugs, such as doxorubicin (DXR), are known to intercalate into nuclear DNA, inhibiting cancer cell growth.
  • The interaction of these DNA intercalators with mitochondrial DNA (mtDNA) is not well understood.

Purpose of the Study:

  • To investigate how DNA intercalators interact with mtDNA within living cells.
  • To elucidate the cellular response to DNA intercalator-induced mtDNA damage.

Main Methods:

  • Cell and molecular studies using cultured cells.
  • Analysis of mitochondrial DNA nucleoid structure and protein distribution.
  • Investigation of mitochondrial morphology and fusion proteins (mitofusin 1, OPA1).
  • Assessment of the role of p53 and ATM in the response.

Main Results:

  • DNA intercalators rapidly intercalate into mtDNA, causing nucleoid aggregation and altered protein distribution.
  • Mitochondrial DNA nucleoids remodel to exclude intercalators and maintain synthesis, while non-remodelled nucleoids experience replication inhibition and mtDNA depletion.
  • Mitochondrial remodeling is linked to mitochondrial elongation/interconnection and suppressed by defects in mitochondrial fusion proteins (mitofusin 1, OPA1).
  • p53 or ATM inhibition enhances nucleoid remodeling, suggesting a link to the genomic DNA damage response.

Conclusions:

  • DNA intercalators trigger a common mitochondrial response involving nucleoid remodeling and altered mitochondrial dynamics.
  • This mitochondrial response may contribute to the clinical toxicity observed with DNA intercalating anticancer drugs.

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