Developing T lymphocytes are uniquely sensitive to a lack of topoisomerase III alpha.
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.
Mönnich
Maren
M
Department of Developmental Immunology, Max-Planck Institute of Immunobiology, Freiburg, Germany.
Hess
Isabell
I
Wiest
Waltraud
W
Bachrati
Csanad
C
Hickson
Ian D
ID
Schorpp
Michael
M
Boehm
Thomas
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D002454:Cell Differentiation / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D008958:Models, Molecular; D011485:Protein Binding; D016415:Sequence Alignment; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D018398:Homeodomain Proteins; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C064658:RAG-1 protein; D004264:DNA Topoisomerases, Type I