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Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
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In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
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Transmitochondrial Cybrid Generation Using Cancer Cell Lines
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Transmitochondrial Cybrid Generation Using Cancer Cell Lines

Published on: March 17, 2023

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
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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.

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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.