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Duplication of ATR inhibits MyoD, induces aneuploidy and eliminates radiation-induced G1 arrest

L Smith1, S J Liu, L Goodrich

  • 1Vollum Institute, Oregon Health Sciences University, Portland 97201, USA.

Nature Genetics
|May 20, 1998
PubMed

Insights

Chromosome 3q alterations, specifically an isochromosome 3q (i(3q)), inhibit muscle differentiation and cell-cycle control. This study links these changes to the ataxia-telangiectasia and rad3-related (ATR) gene, impacting tumor development.

Area of Science:

  • Cancer Biology
  • Genetics
  • Cell Biology

Background:

  • Chromosome 3q alterations are common in various tumors.
  • Rhabdomyosarcomas often exhibit these genetic changes.
  • Muscle differentiation is crucial for normal tissue development.

Purpose of the Study:

  • To investigate the functional consequences of chromosome 3q alterations in muscle cells.
  • To identify specific genes on chromosome 3q involved in tumor development.
  • To understand the role of these alterations in cell cycle regulation and differentiation.

Main Methods:

  • Genetic screening in rhabdomyosarcoma models.
  • Introduction of isochromosome 3q (i(3q)) into myoblasts.
  • Analysis of MyoD function and muscle differentiation markers.
  • Assessment of cell cycle progression, centrosome abnormalities, and DNA damage response.
  • Gene expression analysis of candidate genes within the 3q region.

Main Results:

  • The i(3q) was identified and shown to inhibit muscle differentiation by blocking MyoD.
  • i(3q) induced a 'cut' phenotype, centrosome amplification, aneuploidy, and loss of G1 arrest after irradiation.
  • Forced expression of ataxia-telangiectasia and rad3-related (ATR) mimicked the i(3q) phenotype.
  • Genetic alteration of ATR was directly linked to impaired differentiation and cell cycle defects.

Conclusions:

  • Chromosome 3q alterations, particularly i(3q), disrupt muscle differentiation and cell cycle control.
  • The ataxia-telangiectasia and rad3-related (ATR) gene is a key driver of these phenotypes.
  • ATR's role in differentiation and cell cycle regulation is critical for understanding 3q-driven tumorigenesis.

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