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

TY - JOUR

T1 - Developing T lymphocytes are uniquely sensitive to a lack of topoisomerase III alpha

AU - Mönnich, Maren

AU - Hess, Isabell

AU - Wiest, Waltraud

AU - Bachrati, Csanad

AU - Hickson, Ian D

AU - Schorpp, Michael

AU - Boehm, Thomas

PY - 2010/9

Y1 - 2010/9

N2 - 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.

AB - 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.

KW - Animals

KW - CD4-Positive T-Lymphocytes

KW - Cell Differentiation

KW - DNA Breaks, Double-Stranded

KW - DNA Topoisomerases, Type I

KW - Homeodomain Proteins

KW - Humans

KW - In Situ Hybridization

KW - Models, Molecular

KW - Protein Binding

KW - Sequence Alignment

KW - Sequence Deletion

KW - Tumor Suppressor Protein p53

KW - Zebrafish

KW - Zebrafish Proteins

U2 - 10.1002/eji.201040634

DO - 10.1002/eji.201040634

M3 - Journal article

C2 - 20623552

SN - 0014-2980

VL - 40

SP - 2379

EP - 2384

JO - European Journal of Immunology

JF - European Journal of Immunology

IS - 9

ER -