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Related Concept Videos

Nondisjunction01:29

Nondisjunction

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During meiosis, chromosomes occasionally separate improperly. This occurs due to failure of homologous chromosome separation during meiosis I or failed sister chromatid separation during meiosis II. In some species, notably plants, nondisjunction can result in an organism with an entire additional set of chromosomes, which is called polyploidy. In humans, nondisjunction can occur during male or female gametogenesis and the resulting gametes possess one too many or one too few chromosomes.
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Nondisjunction01:21

Nondisjunction

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Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate correctly and move to the opposite poles of the cells. This produces daughter cells with abnormal chromosome numbers.  Nondisjunction is common during anaphase I or anaphase II of meiosis.  Mutations in synaptonemal complex proteins that attach homologous chromosomes increase the chances of nondisjunction in anaphase I of meiosis I. In contrast, mutations in topoisomerases and condensins that hold...
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Meiosis I01:49

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Meiosis is a carefully orchestrated set of cell divisions, the goal of which—in humans—is to produce haploid sperm or eggs, each containing half the number of chromosomes present in somatic cells elsewhere in the body. Meiosis I is the first such division, and involves several key steps, among them: condensation of replicated chromosomes in diploid cells; the pairing of homologous chromosomes and their exchange of information; and finally, the separation of homologous chromosomes by...
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Chromosomal aberrations, clastogens vs aneugens.

Masayuki Mishima1

  • 1Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, 412-8513, Japan, mishimamsy@chugai-pharm.co.jp.

Frontiers in Bioscience (Scholar Edition)
|November 5, 2016
PubMed
Summary

Anticancer drugs can be genotoxic. A new biomarker, gamma-H2AX, aids in classifying genotoxic outcomes by identifying DNA damage and apoptosis, improving anticancer drug screening.

Area of Science:

  • Biomarkers and Toxicology
  • Cancer Therapeutics
  • Genotoxicity Assessment

Background:

  • Anticancer therapies represent a significant source of genotoxic exposure.
  • Cancer affects a substantial portion of the population in the US, Japan, and Europe.
  • Distinguishing between clastogenicity and aneugenicity is crucial for risk assessment.

Purpose of the Study:

  • To review the integration of the gamma-H2AX biomarker in anticancer drug screening.
  • To elucidate the mode of action (MoA) for genotoxic outcomes.
  • To transition in vitro genotoxicity screening towards MoA elucidation.

Main Methods:

  • Utilizing the gamma-H2AX biomarker in high-throughput assay platforms.
  • Employing additional biomarkers (caspase-3, phosphorylated histone H3) to differentiate gamma-H2AX induction causes.

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  • Developing standard methodologies and consensus thresholds for gamma-H2AX criteria.

    • Main Results:

    • Gamma-H2AX is a sensitive biomarker for DNA double-strand breaks and is induced by apoptosis.
    • Discrimination between relevant and irrelevant gamma-H2AX elevation is achievable using complementary biomarkers.
    • The gamma-H2AX assay platform is adaptable for high-throughput screening.

    Conclusions:

    • Gamma-H2AX shows promise for advancing genotoxicity screening in anticancer drug development.
    • Accurate MoA classification of genotoxic outcomes is essential for effective risk management.
    • Standardization of gamma-H2AX assays will enhance its utility in drug screening.