Genomic instability in Gadd45a-/- cells is coupled with S-phase checkpoint defects

Cell Cycle. 2005 May;4(5):704-9. doi: 10.4161/cc.4.5.1675. Epub 2005 May 14.

Abstract

Gadd45a is a p53-regulated gene whose protein product, like p53, is involved in maintenance of genome stability. Specifically, deletion of Gadd45a leads to extensive aneuploidy as a consequence of centrosome amplification and subsequent abnormal segregation of chromosomes during mitosis. S-phase checkpoints were investigated in Gadd45a(-/-) cells to determine possible defects contributing to the uncoupling of centrosome duplication and DNA replication. In the presence of hydroxyurea, Gadd45a(-/-) mouse embryo fibroblasts show increased centrosome amplification coupled with loss of a sustained S-phase checkpoint. Gadd45a deletion allows another form of genomic instability, gene amplification, when p21 (Cdkn1a gene product) is deleted also. Gene amplification in Gadd45a(-/-)p21(-/-) cells correlated with loss of both G(1) and S-phase checkpoints. Multiple conditions of nutrient deprivation failed to prevent DNA synthesis in Gadd45a(-/-) cells. Gadd45a is therefore required for proper S-phase control and checkpoints under multiple conditions of nutrient deprivation. It is proposed that loss of S-phase control may account for both the uncoupling of DNA replication and centrosome duplication, and conferring gene amplification proficiency in cells lacking Gadd45a(-/-). This is of particular importance for solid tumors, which may lack sufficient nutrients yet are unable to elicit checkpoints preventing genomic instability under these conditions.

MeSH terms

  • Aneuploidy
  • Animals
  • Aspartic Acid / analogs & derivatives
  • Aspartic Acid / pharmacology
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / physiology*
  • Cell Line
  • Centrosome / drug effects
  • Centrosome / physiology
  • Chromosome Segregation
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / physiology
  • DNA / biosynthesis
  • DNA Replication
  • G1 Phase / drug effects
  • G1 Phase / genetics
  • G1 Phase / physiology
  • Gene Amplification
  • Gene Deletion
  • Gene Expression Regulation
  • Genes, cdc* / drug effects
  • Genes, p53
  • Genomic Instability*
  • Hydroxyurea / pharmacology
  • Mice
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / physiology*
  • Phosphonoacetic Acid / analogs & derivatives
  • Phosphonoacetic Acid / pharmacology
  • S Phase / drug effects
  • S Phase / genetics*

Substances

  • Cdkn1a protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Gadd45a protein, mouse
  • Nuclear Proteins
  • Aspartic Acid
  • sparfosic acid
  • DNA
  • Phosphonoacetic Acid
  • Hydroxyurea