Developing T lymphocytes are uniquely sensitive to a lack of topoisomerase III alpha

Eur J Immunol. 2010 Sep;40(9):2379-84. doi: 10.1002/eji.201040634.

Abstract

All organisms possess at least one type IA DNA topoisomerase. These topoisomerases function as part of a DNA structure-specific "dissolvasome," also known as the RTR complex, which has critical functions in faithful DNA replication, recombination, and chromosome segregation. In humans, the heteromeric RTR complex consists of RMI1, RMI2, the Bloom's syndrome gene product (BLM), and topoisomerase 3A (TOP3A) proteins. Here, we describe the identification and characterization of two deleterious mutations in the zebrafish top3a gene that reveal an unexpected tissue-specific requirement of top3a function in developing thymocytes. Deficiency in top3a activates a p53-dependent check-point but does not affect VDJ recombination. Our results suggest that TOP3A could be a candidate gene involved in human primary immunodeficiency syndromes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes
  • Cell Differentiation / genetics
  • DNA Breaks, Double-Stranded*
  • DNA Topoisomerases, Type I / genetics
  • DNA Topoisomerases, Type I / immunology
  • DNA Topoisomerases, Type I / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology
  • Homeodomain Proteins / metabolism*
  • Humans
  • In Situ Hybridization
  • Models, Molecular
  • Protein Binding
  • Sequence Alignment
  • Sequence Deletion
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / immunology
  • Tumor Suppressor Protein p53 / metabolism*
  • Zebrafish
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / immunology
  • Zebrafish Proteins / metabolism*

Substances

  • Homeodomain Proteins
  • Tumor Suppressor Protein p53
  • Zebrafish Proteins
  • RAG-1 protein
  • DNA Topoisomerases, Type I